More than 75% of HIV+ individuals over the age of 50 now die from non-HIV related causes, suggesting that the causes of cognitive impairment among older HIV+ individuals may overlap with those among elderly HIV- individuals. The cause of HIV-associated neurocognitive disorders (HAND) among older HIV+ individuals is not well established and could be due to the HIV virus itself, the earlier onset of neurodegenerative diseases such as Alzheimer's disease (AD) or microvascular ischemic (small stroke) associated cognitive impairment. Based upon previous studies, we hypothesize a new conceptual framework that cerebrovascular disease co-morbidity may contribute to cognitive impairment among HIV+ individuals in the 50-59 year age group and neurodegenerative conditions such as AD and cerebrovascular disease contribute to the increased frequency of cognitive impairment among HIV+ individuals in the ? 60 year subgroup. Positron emission tomography (PET) with [18F] AV-45 to detect increased amyloid uptake, a characteristic finding in AD, can be used to identify the contribution of this specific pathophysiological mechanism for cognitive impairment in older HIV+ individuals and is likely to be available for clinical use in 2012.
The specific aims of our proposal are: 1) to determine whether abnormal amyloid accumulation in brain as measured by PET [18F] AV-45 is present among young, younger aged, and older aged HIV+ individuals, 2) to determine whether abnormal amyloid accumulation in brain is present in older (50-59 year and ? 60 year old) HIV+ individuals with HAND, and 3) to determine whether abnormal amyloid accumulation predicts executive functioning decline in older HIV+ individuals. We hypothesize that 1) PET [18F] AV-45 will be detected in HIV+ individuals, and will be chronologically inappropriate compared to age-matched HIV- individuals, 2) PET [18F] AV-45 will have increased uptake in older HIV+ individuals with HAND compared to older HIV+ individuals without HAND, and 3) increased PET [18F] AV-45 uptake will predict executive functioning decline in older HIV+ individuals. Other novel neuroimaging markers of AD, vascular disease, and abnormal lipid metabolism will also be examined for their association with both PET [18F] AV-45 uptake in HIV+ individuals with HAND, and their ability to predict executive functioning decline. Our proposal will be the first application of [18F] AV-45, a novel radiopharmaceutical tracer, in older HIV+ individuals with and without HAND and age and demographically matched HIV- individuals. Our proposal will increase our understanding of pathogenetic mechanisms of cognitive impairment in both 50-59 year old and ? 60 year old HIV+ individuals with HAND, the latter group an age range not previously examined in detail. The identification and validation of PET AV-45 as a surrogate marker for HAND in older HIV+ individuals could serve to identify patients at risk for cognitive decline, and may identify cellular targets for therapeutic intervention.
In 2015, it is anticipated that 50% of HIV+ individuals will be >age 50 years. This proposal will use a novel PET measure likely available for clinical use in 2012, to determine whether abnormal amyloid deposition is present in the brain at a chronologically inappropriate age in HIV+ individuals, and whether it is associated with cognitive impairment, and executive functioning decline.
|Saylor, Deanna; Dickens, Alex M; Sacktor, Ned et al. (2016) HIV-associated neurocognitive disorder--pathogenesis and prospects for treatment. Nat Rev Neurol 12:234-48|
|Sacktor, Ned; Skolasky, Richard L; Seaberg, Eric et al. (2016) Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology 86:334-40|
|Fazeli, Pariya L; Moore, David J; Franklin, Donald R et al. (2016) Lower CSF AÎ² is Associated with HAND in HIV-Infected Adults with a Family History of Dementia. Curr HIV Res 14:324-30|
|Lu, Lijun; Ma, Jianhua; Feng, Qianjin et al. (2015) Anatomy-guided brain PET imaging incorporating a joint prior model. Phys Med Biol 60:2145-66|
|Sacktor, Ned; Miyahara, Sachiko; Evans, Scott et al. (2014) Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment. J Neurovirol 20:620-6|
|Sacktor, Ned; Robertson, Kevin (2014) Evolving clinical phenotypes in HIV-associated neurocognitive disorders. Curr Opin HIV AIDS 9:517-20|
|Sacktor, Ned; Nakasujja, Noeline; Redd, Andrew D et al. (2014) HIV subtype is not associated with dementia among individuals with moderate and advanced immunosuppression in Kampala, Uganda. Metab Brain Dis 29:261-8|