COORDINATED GENE EXPRESSION OF ARACHIDONIC AND DOCOSAHEXAENOIC ACID CASCADE ENZYMES DURING HUMAN BRAIN DEVELOPMENT AND AGING. The polyunsaturated arachidonic and docosahexaenoic acids (AA and DHA) participate in neuroplasticity and neurotransmission throughout life. We showed that AA and DHA pathway genes are coordinately expressed and underlie cascade interactions during human brain development and aging. We used the publically available BrainCloud database for human non-pathological prefrontal cortex gene expression to quantify postnatal age changes in mRNA expression of 34 genes involved in AA and DHA metabolism. Expression patterns were split into Development (0 to 20 years) and Aging (21 to 78 years) intervals. Expression of genes for cytosolic phospholipases A2 (cPLA2), cyclooxygenases (COX)-1 and -2, and other AA cascade enzymes, correlated closely with age during Development, less so during Aging. Expression of DHA cascade enzymes was less inter-correlated, but often changed in the opposite direction to expression of AA cascade genes. Thus, coordinated age-related gene expression during the brain Development and Aging intervals likely underlies coupled changes in enzymes of the AA and DHA cascades and largely occur through distant transcriptional regulation. Healthy brain aging does not show upregulation of PLA2G4 or PTGS2 expression, which was found in Alzheimer's disease. COORDINATED EXPRESSION OF PHOSPHOINOSITIDE METABOLIC GENES DURING DEVELOPMENT AND AGING OF HUMAN DORSOLATERAL PREFRONTAL CORTEX. Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade. We hypothesized that gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging. We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years) and Aging (21+ years). We identified three groups of partially overlapping genes in each of the two intervals, with similar intergroup correlations despite marked phenotypic differences between Aging and Development. In each interval, ITPKB, PLCD1, PIK3R3, ISYNA1, IMPA2, INPPL1, PI4KB, and AKT1 are in Group 1, PIK3CB, PTEN, PIK3CA, and IMPA1 in Group 2, and SACM1L, PI3KR4, INPP5A, SYNJ1, and PLCB1 in Group 3. Ten of the genes change expression nonlinearly during Development, suggesting involvement in rapidly changing neuronal, glial and myelination events. Correlated transcription for some gene pairs likely is facilitated by colocalization on the same chromosome band. In conclusion, stable coordinated gene transcriptional networks regulate brain phosphoinositide metabolic pathways during human Development and Aging. COORDINATED GENE EXPRESSION OF NEUROINFLAMMATORY AND CELL SIGNALING MARKERS IN DORSOLATERAL PREFRONTAL CORTEX DURING HUMAN BRAIN DEVELOPMENT AND AGING. We hypothesized that expression (mRNA transcript) levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades, and are related to lipid metabolic gene expression. To test this, we used a large-scale microarray dataset from human prefrontal cortex, BrainCloud, to quantify age changes over the lifespan, divided into Development (0 to 21 years, 87 brains) and Aging (22 to 78 years, 144 brains) intervals, in transcription levels of 39 genes. Expression levels followed different trajectories over the lifespan. Many changes were intercorrelated within three groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes could be related to reported neuronal loss, dendritic growth and pruning, and microglial events. TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFKB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. In conclusion, coordinated changes in gene transcription cascades underlie changes in synaptic, neurotrophic, and inflammatory phenotypic networks during brain Development and Aging. Early postnatal expression changes relate to neuronal, glial, and myelin growth and synaptic pruning events, while late Aging is associated with pro-inflammatory and synaptic loss changes. Thus, comparable transcriptional regulatory networks that operate throughout the lifespan underlie different phenotypic processes during Aging compared to Development. SCREENING AND RECRUITMENT FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS (HAND) STUDIES AND AN EVALUATION OF HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS IN VIROLOGICALLY CONTROLLED PATIENTS. I am co-investigator on this ongoing NIH protocol (13-N-014). This 8 year multi-institute screening protocol will identify approximately 200 HIV-infected individuals and 100 healthy volunteers for enrollment in multiple HAND studies at the NIH. Subjects undergo a one-time screening and evaluation assessment, which includes neuropsychological testing, brain magnetic resonance imaging (MRI), positron emission tomography (PET) and cerebrospinal fluid (CSF) sampling for virus and inflammatory biomarkers. This observational study will characterize the natural course of HAND in subjects with HIV viral loads < 50 copies/mm3. It should enhance understanding of the CNS as a potential HIV reservoir in virally controlled individuals and help in identifying biomarkers and new therapeutic interventions (see below). This NIH screening protocol also is coordinated with a similar screening protocol on different patient and controls at the USUHS, on which I also am co-investigator. ANAKINRA, A RECOMBINANT HUMAN IL-1 RECEPTOR ANTAGONIST, FOR TREATING NEUROINFLAMMATION IN HIV-1 INFECTION. Based on my suggestion, the multicenter HIV-1 study group at the NIH has written a protocol that recently has been approved by the NIAID and CNS IRBs, to perform a Phase I trial with the interleukin (IL)-1 receptor (IL-1R) antagonist, Anakinra. The protocol is partly funded by a $100,000 Bench to Bedside Award to us. Anakinra is licensed by the FDA, crosses the BBB, has demonstrated safety and efficacy in a number of inflammatory diseases (e.g., rheumatoid arthritis and neonatal onset multisystem inflammatory disorder (NOMID)), and may mitigate neuroinflammation in HAND. We first will conduct a Phase 1 pilot study with Anakinra to address its safety in patients with HAND. The study will be conducted at the NIH Clinical Center and the Johns Hopkins University Department of Neurology. Twelve volunteers with HAND will self-administer daily injections of Anakinra for 8 weeks. Safety will be assessed throughout treatment and afterwards. The study should start before the end of the year. MIGRAINE AS A BIOMARKER OF NEUROINFLAMMATION AND HAND IN HIV-1. On the basis of my review of the literature, I proposed to the HIV-1 research group that migraine headache should be evaluated as a potential biomarker of neuroinflammation in HAND. The prevalence of migraine in HIV-1 patients on antiretroviral therapy (ACT) approximates 50%, compared with 5-15% in the general population, and both migraine and HIV-1 are characterized by neuroinflammation -- increased cytokines and upregulated brain arachidonic acid metabolism. Accordingly, specific migraine questionnaires have been added to the NIH screening protocol, and we are preparing a publication to elaborate the hypothesis.
Showing the most recent 10 out of 18 publications
