Risk factors found in cerebrospinal fluid increase the likelihood that individuals with HIV disease will develop dementia or other neurocognitive disorders.
In September the World Health Organization reported a 21 percent drop in HIV-related deaths since 2008. Though advancements in antiretroviral (ARV) therapies have contributed significantly to this decrease, ARV therapies have not reduced the rates of HIV-associated neurocognitive disorders (HAND), which can put infected individuals at a higher risk for mortality.
Norman Haughey, Ph.D., an associate professor in the Department of Neurobiology and Psychiatry at Johns Hopkins University School of Medicine, led an investigation to identify metabolic factors that may contribute to HAND.
“Approximately 50 percent of HIV-infected subjects will develop some form of mild cognitive impairment—ranging from difficulties in counting money to frank dementia,” Haughey told Psychiatric News. “We don’t understand why—despite adequate viral suppression by antiretroviral therapies—some subjects still develop cognitive impairment. Our [recent] work has begun to unravel the molecular aspect of neurocognitive decline, which pointed us toward lysosomes.”
Approximately 50 percent of HIV-infected individuals experience neurocognitive decline, along with dyslipidemia in peripheral tissues. Researchers studied the relationship to cognitive decline of HIV infection, antiretroviral therapies, and fat content in the central nervous system. They found that
HIV infection increases cholesterol in cerebral spinal fluid (CSF).
Antiretroviral drugs—in particular nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs)—further increase CSF cholesterol content.
Alterations in the fat derivatives sphingomyelin and cholesterol esters were predictive of the onset of HIV-associated neurocognitive disorder.
Researchers hope that early detection of CSF lipid profiles for neurocognitive disorders in people with HIV will prompt a regimen of neuroprotective therapies before cognition declines.
Lysosomes are responsible for breakdown of waste and metabolites, such as lipids, in cells. When lysosomes are dysfunctional, it can be damaging for neurons and other cells, leading to profiles similar to that of lysosomal storage disorder—which is defined by lipid accumulation.
“Dyslipidemia is common in HIV-infected individuals, and in some cases this condition is increased by ARV medications,” said Haughey. He explained that HIV-associated dyslipidemia is most often noted in the blood and is characterized by elevated levels of cholesterol and other fat derivatives, such as sphingomyelin, that affect the cardiovascular, renovascular, and neurovascular systems.
“What has not been reported,” he added, “is that these [fat derivatives] are also elevated in the cerebrospinal fluid [CSF].”
In the current study, published September 11 in Neurology, Haughey and colleagues enrolled 291 HIV-positive and 30 HIV-negative individuals to assess the correlation between CSF lipid content and ARV therapies with HAND progression. The longitudinal study was performed at seven U.S. sites, including ones in Hawaii and Puerto Rico, to ensure that the study population was diverse.
CSF was collected from each participant and evaluated for cholesterol and sphingomyelin concentrations. Cognitive impairment was measured by the Memorial Sloan-Kettering (MSK) Dementia Severity Scale. Participants were measured on all parameters at baseline and during a one-year follow-up.
ARV drug classes prescribed to treat HIV infection included protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and integrase inhibitors.
At baseline, HIV-positive individuals could be distinguished from controls by elevated levels of CSF cholesterol, which was further increased by an average of 50 percent by ARV therapy—in particular, NRTIs and NNRTIs. There was no difference in overall MSK scale scores among subjects from baseline to follow-up.
At follow-up, elevation of a single sphingomyelin and reduction of cholesterol esters, a less water-soluble form of cholesterol, were predictive indicators for the onset of HAND in the HIV-infected cohort.
“This suggests that this dyslipidemia that occurs in the periphery may also occur in the central nervous system and seems to be related to a particular class of drugs,” said Haughey. He noted that NRTIs and NNRTIs are generally the first line of therapy for HIV viral suppression.
“Prior to ARV therapy, neurocognitive impairment occurred at a quicker rate and was very progressive. After ARV [therapies], there was still a forward progression, but it was milder,” he explained. “People are living longer, and impairment onset is variable.”
When asked about the clinical implications of his research, Haughey said, “It’s good to remember that rates of cognitive impairment [in HIV-infected individuals] are quite high. The rates of comorbid depression and other psychiatric disorders are also quite high, and sometimes it’s difficult to tease these conditions out. From our studies we hope to have a biomarker that can be identified very early in HIV [positive] subjects who seem perfectly normal by any cognitive test but whose lipid profiles indicate that they are at risk for cognitive impairment.”
“Neuroprotective therapy works best prior to neurocognitive damage….Several trials have failed trying to reverse it,” he concluded.
The study was funded by the National Institutes of Health. ■
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