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A lipid storage-like disorder contributes to
cognitive decline in HIV-infected subjects
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Download the PDF here
Download the PDF here
"These findings suggest that therapeutics targeting sphingolipid or sterol metabolism may preserve lysosomal function in HIV. For example, pretreatment of neurons with HMG-coenzyme A reductase inhibitors (the rate-limiting enzyme for cholesterol synthesis) has been shown to protect neurons from HIV by reducing the induction of stress-associated pathways including Hsp70, isoprostanes, and total nitrate levels. 29 A second intriguing possibility is that dietary manipulations could modify brain sphingolipid and sterol content. Age-associated accumulations of ceramides and long-chain glycosphingolipids can be reduced by caloric restriction, or by a diet rich in n-3 polyunsaturated fatty acids.30,31 In contrast, diets high in fat, cholesterol, and sugar elevated galacto sylceramide and sphingomyelin levels in hippocampus, and were associated with increased oxidative stress.32 Thus, both dietary and pharmacologic interventions could potentially restore brain sphingolipid and sterol balance in HIV-infected individuals, and may preserve the function of endolysosomal systems."
Abstract
Objective: In this multicenter cohort study, we sought to identify prognostic and associative metabolic indicators for HIV-associated neurocognitive disorders (HAND).
Methods: A quantitative lipidomic analysis was conducted on 524 longitudinal CSF samples collected from 7 different performance sites across the mainland United States, Hawaii, and Puerto Rico. Subjects included HIV-infected individuals with longitudinal clinical and cognitive testing data and cognitively normal HIV-negative healthy controls.
Results: At baseline, HIV+ subjects could be differentiated from HIV- controls by reductions in a single ceramide species and increases in multiple forms of cholesterol. Perturbations in cholesterol metabolism and ceramide were influenced by combined antiretroviral therapy (cART) use. There were no cross-sectional baseline differences in any lipid metabolite when HIV+ subjects were grouped according to cognitive status. However, a single sphingolipid metabolite and reduced levels of esterified cholesterols were prognostic indicators of incident cognitive decline. Longitudinal patterns of these disturbances in sphingolipid and sterol metabolism suggest that a progressive disorder of lipid metabolism that is similar to disorders of lipid storage may contribute to the pathogenesis of HAND.
Conclusions: These findings suggest that HIV infection and cART are independently associated with a CNS metabolic disturbance, identify surrogate markers that are prognostic for cognitive decline, and implicate a lipid storage-like disorder in the progression of HAND.
EDITORIAL
Lipids and cognition make good bedfellows for neuroAIDS
Harris A. Gelbard, MD, PhD
Howard E. Gendelman, MD
During a recent discussion of HIV-1-associated neurocognitive deficits (HAND), a colleague whispered across the 2 empty seats of a large auditorium to
ask a simple but profound question, "So what causes HIV cognitive impairment? "Over 20 years ago, the answer might have been, "It's the virus, stupid." Now, there isn't a pat answer.
As a result of highly efficacious combination antiretroviral therapy (cART), HIV-associated dementia is no longer a death sentence for an HIV-infected person.1
The nosologic umbrella we call HAND is caused by a spectrum of pathogenic processes linked to the virus and disruption of normal synaptic communication.2,3 Cognitive dysfunction may also be associated with drugs of abuse, peripheral metabolic disorders, concurrent illnesses including opportunistic infections, inadequate nutrition, liver failure, antiretroviral drug toxicities, immune dysregulation, depression, and other psychiatric maladies.4 The search for specific biomarkers to gauge the severity of HAND and its response to treatment is confounded by these factors, but also by our evolving understanding of viral neuropathogenesis in the CNS, an immunologically protected "sanctuary" or "reservoir" site of residual infection. The virus thus remains a critical determinant in our pursuit of disease eradication. 5 The study in the current issue of Neurology by Bandaru et al.6 appears to have found at least one answer.
In the study, lipidomic techniques (i.e., the quantitative study of biochemical pathways and networks of cellular lipids in biological systems) were used to evaluate CSF from infected people who were either cognitively normal or had neurologic deficits ranging from mild cognitive impairment to moderate dementia, and seronegative, cognitively normal people followed at 7 clinical research centers. HIV-seronegative controls could be differentiated from infected people by reductions in a single ceramide species and increases in multiple forms of cholesterol. Importantly, cART influenced the changes in cholesterol metabolism. No cross-sectional differences in lipid metabolites were seen according to cognitive status. There were also no correlations between CSF levels
of sphingolipid metabolite (SM) (i.e., lipids containing open carbon chains with the am ino alcohol sphingosine), ceramide (N-acyl precursor of sphingosine), or sterols and CD4 cell count, CD4 nadir, and plasma or CSF viral loads. Higher baseline levels of triglycerides were associated with a greater probability of cognitive improvement in follow-up visits within a year. However, a single SM and reduced levels of esterified cholesterols were indicators of cognitive decline. The observations have parallels to lipid profiles associated with lipid storage disorders, raising the question of whether dietary and pharmacologic interventions could restore brain lipid balance in HIV-infected individuals.
The data presented are exciting because they raise the possibility of biomarkers that may provide us with surrogates for assessing the complex and sometimes contrary or fluctuating cognitive changes that occur in patients with HAND. Even more important, these biomarkers might allow us to assess efficacy of new CNS-oriented therapeutic approaches directed at neuroinflammation and normal synaptic function, the substrate of HAND. However, many of the comorbidities that exist with HIV-1 brain infection can affect cognitive decline and are likely to contribute to changes in lipidomic profiles.
These comorbid etiologies must be carefully sorted out. Each of these factors alone or in tandem could alter lipid metabolism. How this occurs in the setting of advanced HIV infection and stable cART remains unclear.
First, it's the macrophage.7 Secretory products from the immune response and HIV-infected mononuclear phagocytes (MP; microglia and bloodborne perivascular macrophages) could be important culprits.8 Indeed, HIV-infected MP, rather than CD41 lymphocytes, are responsible for the spread and persistence of HIV infection within the CNS and certainly mediate neuronal injury and death in CNS disease. 9,10 Second, we cannot ignore persistent immune activation that occurs through the trafficking of CD141/CD161 macro- phages. Perivascular macrophages have a high rate of trafficking between peripheral blood and brain and contribute to the evolution of viral population compartments.11 Third, the CNS viral "sanctuary" has effects on viral kinetics but also allows immunemediated effects on lipid metabolism. This includes the inflammatory factors and viral proteins secreted as a consequence of immune activation.12 Fourth, differences in cART CNS penetration could reflect changes in "micro"-foci of HIV-1 infection in patients in whom parenchymal microglia harbor more long-lived reservoirs13 that could be responsible not only for altered lipid metabolic rates but subsequent neuronal injury. The authors advance a very provocative hypothesis, and their findings are strikingly similar to lysosomal storage diseases that result from inborn errors of lipid metabolism in the pediatric population; all are characterized by inexorably progressive loss of CNS function. This may provide considerable impetus to explore the basis for white matter changes in HAND where viral loads are well-controlled by cART. It does not, however, address the fact that HAND does not follow the unipolar progression to death that is the outcome of these inborn errors of metabolism.
This study gives us a framework for lipidomic biomarker signatures associated with HAND and provides fresh insights into the progression of HAND and the
consequences of cART. But it also raises more questions as we face the continuance of a disease that is far more complex than that solely due to the viral infection within the CNS,which brings us back to where we started: drugs of abuse, concurrent illnesses (CNS and periphe- ral), and altered metabolism may all have regional CNS heterogeneity that can influence HAND clinical phenotypes. We must continue to focus on what happens to the entire CNS and peripheral ecosystem as people treated with cART continue to live and age with HIV-1. The challenges that lie ahead rest in embracing the complexities of interpreting biomarkers in chronic diseases, not simply for diagnostic and prognostic purposes, but utilizing the insights they provide for the pathophysiology and efforts to find clinically useful therapies to eradicate the virus along with the residual and unavoidable damage to the CNS.
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A lipid storage-like disorder contributes to cognitive decline in HIV-infected subjects
Veera Venkata Ratnam Bandaru, Michelle M. Mielke, Ned Sacktor, et al.
Neurology published online September 11, 2013
The widespread use of combined antiretroviral therapy (cART) in developed countries has dramatically decreased the death rates due to AIDS and decreased the incidence of dementia.1,2 However, cART has not reduced the prevalence rates for milder forms of HIV-associated neurocognitive disorders (HAND) that are associated with increased mortality.3-6 HAND frequently manifests in the domains of memory and executive functions,7 and is associated with decreased adherence to pharmacotherapy, lower cognitive reserve, and increased incidence of psychiatric comorbidities.8,9 Despite cART, there is evidence for ongoing neurologic damage that includes persistent astrocyte infection, brain volume loss, inflammation, synaptodendritic damage, and disruptions in white matter integrity.5,10-12 The mechanisms underlying these residual neuropathologic impairments remain obscure.
Several studies have suggested that dysregulations in CNS lipid metabolism may be involved in the pathogenesis of HAND.13-15 In particular, roles for ceramides, sphingomyelins, and cholesterol have been described, but the interrelationships of these bioactive lipids to the temporal progression of HAND have not been determined. In this study, we sought to elucidate the interactions between CSF lipidoses and temporal shifts in the cognitive status of a demographically diverse multicenter collection of HIV-infected subjects. Our findings provide evidence that the onset and progression of HAND involves a progressive disturbance in sphingolipid and cholesterol metabolism that is reminiscent of the biochemical manifestations associated with a lysosomal storage disorder.
"........cART use was associated with higher baseline levels of cholesterol and nearly all cholesterol esters (p , 0.05 or greater). When we separated cART by drug class, we found that nucleoside reverse transcriptase inhibitors and NNRTIs were associated with higher mean levels of multiple forms of cholesterol (p , 0.05; table e-2). Protease, fusion, or integrase inhibitors were not associated with CSF levels of SM, ceramides, or sterols...."
"......Total sterol concentrations in CSF were greater in HIV1 compared with HIV2 subjects (table 2). Compared with HIV2 subjects, HIV1 individuals showed higher levels of all but one sterol species measured including cholesterol, multiple esterified forms of cholesterol, and triglyceride (table 2)....."
"There were 19 subjects taking a statin at baseline. Statin use itself was not a prognostic or associative indicator of worsening or improvement in cognitive status....."
"......a higher SM/ceramide ratio for C24:1 at baseline was associated with a reduced odds of cognitive decline at the next visit (OR 0.06....."
".......Analyzing each of these metabolites separately revealed that higher levels of ceramide C24:1 at baseline were associated with greater odds of cognitive decline (OR 1.31, 95% CI 0.91-1.88; table e-5 and figure 1B), while SMC24:1 was not associated with cognitive decline (OR 0.94, 95% CI 0.70-1.26)......"
"Progressive dysregulations in sphingolipid and sterol metabolism are associated with cognitive decline and metabolic normalization is associated with cognitive improvement."
DISCUSSION (excerpts)
Our data suggest that disturbances in CSF lipid metabolites are a common feature of HAND. The CNS normally has the highest cholesterol content in humans, with daily turnover rates estimated to be approximately 20% of the total brain cholesterol content.18 While this high turnover rate permits rapid plasma membrane turnover and remodeling, excess cholesterol can be sequestered into endosomal/lysosomal compartments. For example, genetic mutations in Niemann-Pick disease, type C1 leads to the sequestration of unesterified cholesterols in endosomal/lysosomal compartments, culminating in the development of pulmonary, hepatic, and neurodegenerative disease. Although cART has been associated with metabolic disturbances that include elevated blood cholesterol and triglycerides,19-21 effects on CSF lipids were unknown. We found HIV infection increased CSF cholesterol ester content, and this was further increased by cART. Moreover, and perhaps surprisingly en face, we found that decreased cholesterol esters were associated with increased risk for cognitive decline. Since increased cholesterol production is balanced by esterification, we interpret these data to suggest that HIV and cART are independently associated with brain cholesterol accumulation. Consistent with this concept of sterol clearance, we found that increased CSF triglycerides were prognostic indicators for cognitive improvement, suggesting that removal of sterols from brain in the form of triglycerides improves cognition.
These metabolites were not associated with cognitive status in cross-sectional comparisons, suggesting that the progression of HAND involves temporal patterns of metabolic disturbance. This abnormal pattern of lipid metabolism in HIV-infected subjects is similar to metabolic disturbances associated with lysosomal storage diseases.
These findings suggest that therapeutics targeting sphingolipid or sterol metabolism may preserve lysosomal function in HIV. For example, pretreatment of neurons with HMG-coenzyme A reductase inhibitors (the rate-limiting enzyme for cholesterol synthesis) has been shown to protect neurons from HIV by reducing the induction of stress-associated pathways including Hsp70, isoprostanes, and total nitrate levels. 29 A second intriguing possibility is that dietary manipulations could modify brain sphingolipid and sterol content. Age-associated accumulations of ceramides and long-chain glycosphingolipids can be reduced by caloric restriction, or by a diet rich in n-3 polyunsaturated fatty acids.30,31 In contrast, diets high in fat, cholesterol, and sugar elevated galacto sylceramide and sphingomyelin levels in hippocampus, and were associated with increased oxidative stress.32 Thus, both dietary and pharmacologic interventions could potentially restore brain sphingolipid and sterol balance in HIV-infected individuals, and may preserve the function of endolysosomal systems.
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