HIV Encephalitis Research Articles

Antiretroviral-treated HIV-1 patients can harbour resistant viruses in CSF despite an undetectable viral load in plasma.

HIV therapy reduces the CSF HIV RNA viral load (VL) and prevents disorders related to HIV encephalitis. However, these brain disorders may persist in some cases. A large population of antiretroviral-treated patients who had a VL > 1.7 log 10 copies/mL in CSF with detectable or undetectable VL in plasma associated with cognitive impairment was studied, in order to characterize discriminatory factors of these two patient populations. Blood and CSF samples were collected at the time of neurological disorders for 227 patients in 22 centres in France and 1 centre in Switzerland. Genotypic HIV resistance tests were performed on CSF. The genotypic susceptibility score was calculated according to the last Agence Nationale de Recherche sur le Sida et les hépatites virales Action Coordonnée 11 (ANRS AC11) genotype interpretation algorithm. Among the 227 studied patients with VL > 1.7 log 10 copies/mL in CSF, 195 had VL detectable in plasma [median (IQR) HIV RNA was 3.7 (2.7-4.7) log 10 copies/mL] and 32 had discordant VL in plasma (VL < 1.7 log 10 copies/mL). The CSF VL was lower (median 2.8 versus 4.0 log 10 copies/mL; P < 0.001) and the CD4 cell count was higher (median 476 versus 214 cells/mm 3 ; P < 0.001) in the group of patients with VL < 1.7 log 10 copies/mL in plasma compared with patients with plasma VL > 1.7 log 10 copies/mL. Resistance to antiretrovirals was observed in CSF for the two groups of patients. Fourteen percent of this population of patients with cognitive impairment and detectable VL in CSF had well controlled VL in plasma. Thus, it is important to explore CSF HIV (VL and genotype) even if the HIV VL is controlled in plasma because HIV resistance may be observed.

Gene expression patterns associated with neurological disease in human HIV infection

The pathogenesis and nosology of HIV-associated neurological disease (HAND) remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI) in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE) and control subjects. The Gene Set Enrichment Analysis (GSEA) algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb). We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC), which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN), cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV infection and identify better therapeutic targets for NCI.

Cytomegalovirus Encephalitis in an Infant; MRI Manifestation: A Clinical Image

Clinical Image: A 7- month old male infant and a known case of cerebral palsy (CP) because of perinatal infection was referred to our academic Taleghani children hospital(Gorgan, Northern Iran), due to inability to intake food percutaneous insertion of gastrostomy tube was planned for him. In a retrograde investigation, we noticed his post natal brain Magnetic Resonance Imaging (MRI) (Figure 1). It illustrates severe hypoxic ischemic change of hemispheres, hydrocephalus, white matter signal abnormality predominantly in posterior regions esp. in parieto-temporal lobes and encephalomalacic cysts esp. in temporal poles; His MRI also depicted atrophy of caudate nuclei and T2 hypersignal intensity of thalami. In addition to above radiologic findings, urine quantitative real-time PCR was positive for CMV with a DNA viral load of 143700 IU/ml. All these findings were highly suggestive for cystic encephalopathy due to CMV (TORCH classification) infection of the brain for this infant. He was born symptom-free from repeated cesarean-section (RCS) of a term non-complicated pregnancy with a birth weight of 3900 g, appropriate for gestational age in a Turkmen family from a consanguineous marriage. His drug history consisted of phenytoin (5 mg/kg/day). CMV is the most common cause of intra-uterine infection and most common cause of congenital infective brain damage, occurring in 0.2-2.4% of live births. The vast majority (90%) of infected babies are asymptomatic at birth, but some may develop symptoms after 6-9 months [1]. Some of MRI findings include [2]: • White matter lesions: Predominantly parietal or posterior white matter involvement • Ventriculomegaly and subarachnoid space enlargement • Delayed myelination • Periventricular and temporal pole cysts The Differential diagnosis include HIV encephalitis, progressive multifocal leukoencephalitis (PML) and primary CNS lymphoma (periventricular but has mass effect and enhances). Primary stabilizing measures were undertaken for our patient. No more abnormality was found in laboratory tests. His PEG tube was inserted successfully and the infant was discharged after acceptable clinical condition.

The chitinases expression is related to Simian Immunodeficiency Virus Encephalitis (SIVE) and in HIV encephalitis (HIVE)

ObjectivesHuman Immunodeficiency Virus (HIV) infection can induce neurocognitive complications classified as HIV-associated neurocognitive disorder (HAND). The chitinase family is associated with innate immunity cells and many infectious diseases. MethodsWe analyzed microarray datasets obtained from NCBI in order to verify the expression of chitinase family genes in hippocampus of uninfected rhesus macaques versus those with histopathologic evidence of Simian Immunodeficiency Virus Encephalitis (SIVE). Moreover, we have analysed two human microarray datasets to verify the results obtained in macaques hippocampus affected by SIVE. For these studies, we have also used the open source tools Genome-scale Integrated Analysis of gene Networks in Tissues (GIANT) to identify the chitinase genes network. ResultsCHIT1, CHI3L1 and CHI3L2 levels were significantly increased in SIVE hippocampus as compared to non-infected control specimens. Furthermore, we found a negative correlation between CHIA vs. Brain Viral Load (BVL). These data was confirmed partially in human brain section of HAD/HIVE subjects. Also, we showed that HIV-1 was able to modulate the expression of CHIT1, CHI3L1, CHI3L2 and CHID1 in human macrophages. ConclusionsThese results suggest that chitinase gene expression is altered in SIVE and in HAD/HIVE brain sections and call for more studies examining whether this is a protective immunological reaction or a destructive tissue response to encephalitis.

Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques.

The aim of the present study was to investigate if macrophage proliferation occurs in the brain during simian immunodeficiency virus (SIV) infection of adult macaques. We examined the expression of the Ki-67 proliferation marker in the brains of uninfected and SIV-infected macaques with or without encephalitis. Double-label immunohistochemistry using antibodies against the pan-macrophage marker CD68 and Ki-67 showed that there was a significant increase in CD68+Ki-67+ cells in macaques with SIV encephalitis (SIVE) compared to uninfected and SIV-infected animals without encephalitis, a trend that was also confirmed in brain samples from patients with HIV encephalitis. Multi-label immunofluorescence for CD163 and Ki-67 confirmed that the vast majority of Ki-67+ nuclei were localized to CD163+ macrophages in perivascular cuffs and lesions. The proliferative capacity of Ki-67+ perivascular macrophages (PVM) was confirmed by their nuclear incorporation of bromodeoxyuridine. Examining SIVE lesions, using double-label immunofluorescence with antibodies against SIV-Gag-p28 and Ki-67, showed that the population of Ki-67+ cells were productively infected and expanded proportionally with lesions. Altogether, this study shows that there are subpopulations of resident PVM that express Ki-67 and are SIV-infected, suggesting a mechanism of macrophage accumulation in the brain via PVM proliferation.

Decrease of aquaporin-4 and excitatory amino acid transporter-2 indicate astrocyte dysfunction for pathogenesis of cortical degeneration in HIV-associated neurocognitive disorders.

Human immunodeficiency virus (HIV) encephalitis and degeneration of cerebral cortex are established histopathologies of HIV-associated neurocognitive disorders (HAND). We previously reported decreased excitatory amino acid transporter-2 (EAAT-2) and astrocytic apoptosis in cortical degeneration using SIVmac239 and simian-human immunodeficiency virus (SHIV)-infected macaques and human AIDS autopsy cases. In the present study, we added highly pathogenic SIVsm543-3-infected macaques. These animals showed similar degenerative changes in the frontal cortex. Using 11 SIV-infected macaques, three SIVsm543-3, five SIVmac239 and three SHIV, we compared brain pathology caused by three different viruses and further analyzed the pathogenic process of HAND. We noticed vacuolar changes in perivascular processes of astrocytes by electron microscopy, and examined expression of astrocyte-specific protein aquaporin-4 (AQP4) by immunohistochemistry. APQ4 was diffusely positive in the neuropil and perivascular area in control brains. There was patchy or diffuse decrease of AQP4 staining in the neuropil of SIV-infected macaques, which was associated with EAAT-2 staining by double immunostaining. A quantitative analysis demonstrated significant positive correlation between areas of AQP4 and EAAT-2. Some astrocytes express EAAT-2 but not AQP4, and decrease of EAAT-2 expression tended to be less than the decrease of AQP4. Active-caspase-3 immunostaining demonstrated apoptosis of neurons and astrocytes in the area of AQP4/EAAT-2 reduction. These results suggest that AQP4 is damaged first and decrease of EAAT-2 may follow in pathogenesis of cortical degeneration. This is the first demonstration of decrease of AQP4 and its association with EAAT-2 decrease in AIDS brain, suggesting a role in the pathogenesis of HAND.

β-Adrenergic receptor gene expression in HIV-associated neurocognitive impairment and encephalitis: implications for MOR-1K subcellular localization.

We previously reported that mRNA expression of the unique alternatively spliced OPRM1 isoform μ-opioid receptor-1K (MOR-1K), which exhibits excitatory cellular signaling, is elevated in HIV-infected individuals with combined neurocognitive impairment (NCI) and HIV encephalitis (HIVE). It has recently been shown that the β2-adrenergic receptor (β2-AR) chaperones MOR-1K, normally localized intracellularly, to the cell surface. Here, we found mRNA expression of the adrenoceptor beta 2 (ADRB2) gene is also elevated in NCI-HIVE individuals, as well as that β2-AR protein expression is elevated in HIV-1-infected primary human astrocytes treated with morphine, and discuss the implications for MOR-1K subcellular localization in this condition.

Lifetime methamphetamine dependence is associated with cerebral microgliosis in HIV-1-infected adults.

Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), β-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95% confidence interval, 1.36, 14.39), p = 0.014, n = 62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n = 61); hepatitis C virus seropositivity (n = 54); and lifetime dependence on alcohol, opiates, and cannabis (n = 62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, β-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.

Cerebrospinal Fluid Biomarkers of Simian Immunodeficiency Virus Encephalitis : CSF Biomarkers of SIV Encephalitis.

Antiretroviral therapy has led to increased survival of HIV-infected patients but also increased prevalence of HIV-associated neurocognitive disorders. We previously identified YKL40 as a potential cerebrospinal fluid (CSF) biomarker of lentiviral central nervous system (CNS) disease in HIV-infected patients and in the macaque model of HIV encephalitis. The aim of this study was to define the specificity and sensitivity along with the predictive value of YKL40 as a biomarker of encephalitis and to assess its relationship to CSF viral load. CSF YKL40 and SIV RNA concentrations were analyzed over the course of infection in 19 SIV-infected pigtailed macaques and statistical analyses were performed to evaluate the relationship to encephalitis. Using these relationships, CSF alterations of 31 neuroimmune markers were studied pre-infection, during acute and asymptomatic infection, at the onset of encephalitis, and at necropsy. YKL40 CSF concentrations above 1122ng/ml were found to be a specific and sensitive biomarker for the presence of encephalitis and were highly correlated with CSF viral load. Macaques that developed encephalitis had evidence of chronic CNS immune activation during early, asymptomatic, and end stages of infection. At the onset of encephalitis, CSF demonstrated a rise of neuroimmune markers associated with macrophage recruitment, activation and interferon response. CSF YKL40 concentration and viral load are valuable biomarkers to define the onset of encephalitis. Chronic CNS immune activation precedes the development of encephalitis while some responses suggest protection from CNS lentiviral disease.

Editorial: HIV and Illicit Drugs of Abuse.

Editorial: HIV and Illicit Drugs of Abuse.

The HIV Protein gp120 Alters Mitochondrial Dynamics in Neurons.

Neurotoxicity of human immunodeficiency virus-1 (HIV) includes synaptic simplification and neuronal apoptosis. However, the mechanisms of HIV-associated neurotoxicity remain unclear, thus precluding an effective treatment of the neurological complications. The present study was undertaken to characterize novel mechanisms of HIV neurotoxicity that may explain how HIV subjects develop neuronal degeneration. Several neurodegenerative disorders are characterized by mitochondrial dysfunction; therefore, we hypothesized that HIV promotes mitochondrial damage. We first analyzed brains from HIV encephalitis (HIVE) by electron microscopy. Several sections of HIVE subjects contained enlarged and damaged mitochondria compared to brains from HIV subjects with no neurological complications. Similar pathologies were observed in mice overexpressing the HIV protein gp120, suggesting that this viral protein may be responsible for mitochondrial pathology found in HIVE. To gain more information about the cellular mechanisms of gp120 neurotoxicity, we exposed rat cortical neurons to gp120 and we determined cellular oxygen consumption rate, mitochondrial distribution, and trafficking. Our data show that gp120 evokes impairment in mitochondrial function and distribution. These data suggest that one of the mechanisms of HIV neurotoxicity includes altered mitochondrial dynamics in neurons.

The Pathogenesis of HIV-Associated Dementia: Recent Advances Using a SCID Mouse Model of HIV-Encephalitis

In the era of highly active antiretroviral therapy (HAART) there has been a decrease in AIDS death rates and a reduction in HIV-related neurological complications. However, Human Immunodeficiency Virus-1 (HIV)-associated dementia (HAD) still affects at least 7% of HIV-positive individuals. Despite significant advances in HIV research there are still questions surrounding the pathogenesis of HAD. Clinical information and pathological studies suggest that the frontal cortex, basal ganglia, and hippocampus are important neuroanatomical areas involved in HAD. Recent studies utilizing a severe combined immunodeficiency (SCID) mouse model of HIV-encephalitis (HIVE) indicate that central nervous system (CNS) viral load determines the severity of astrogliosis, an important feature of HIVE. Human and animal studies suggest that viral strains may also be important in the pathogenesis of HAD. A recent study suggests that HAART does not eradicate virus in the brain, and therefore, the CNS is a reservoir for HIV. Future research efforts need to focus on the role of viral strain and mutations in the pathogenesis of HAD.

The Janus kinase inhibitor ruxolitinib reduces HIV replication in human macrophages and ameliorates HIV encephalitis in a murine model

A hallmark of persistent HIV-1 infection in the central nervous system is increased activation of mononuclear phagocytes and surrounding astrogliosis, conferring persistent HIV-induced inflammation. This inflammation is believed to result in neuronal dysfunction and the clinical manifestations of HIV-associated neurocognitive disorders (HAND). The Jak/STAT pathway is activated in macrophages/myeloid cells upon HIV-1 infection, modulating many pro-inflammatory pathways that result in HAND, thereby representing an attractive cellular target. Thus, the impact of ruxolitinib, a Janus Kinase (Jak) 1/2 inhibitor that is FDA approved for myelofibrosis and polycythemia vera, was assessed for its potential to inhibit HIV-1 replication in macrophages and HIV-induced activation in monocytes/macrophages in culture. In addition, a murine model of HIV encephalitis (HIVE) was used to assess the impact of ruxolitinib on histopathological features of HIVE, brain viral load, as well as its ability to penetrate the blood–brain-barrier (BBB). Ruxolitinib was found to inhibit HIV-1 replication in macrophages, HIV-induced activation of monocytes (CD14/CD16) and macrophages (HLA-DR, CCR5, and CD163) without apparent toxicity. In vivo, systemically administered ruxolitinib was detected in the brain during HIVE in SCID mice and markedly inhibited astrogliosis. Together, these data indicate that ruxolitinib reduces HIV-induced activation and infiltration of monocytes/macrophages in vitro, reduces the replication of HIV in vitro, penetrates the BBB when systemically administered in mice and reduces astrogliosis in the brains of mice with HIVE. These data suggest that ruxolitinib will be useful as a novel therapeutic to treat humans with HAND.

Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection.

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high in patients with effective suppression of virus replication by combination antiretroviral therapy (cART). Several neurotransmitter systems were reported to be abnormal in HIV-infected patients, including the inhibitory GABAergic system, which mediates fine-tuning of neuronal processing and plays an essential role in cognitive functioning. To elucidate the role of abnormal GABAergic transmission in HAND, the expression of GABAergic markers was measured in 449 human brain specimens from HIV-infected patients with and without HAND. Using real-time polymerase chain reaction, immunoblotting and immunohistochemistry we found that the GABAergic markers were significantly decreased in most sectors of cerebral neocortex, the neostriatum, and the cerebellum of HIV-infected subjects. Low GABAergic expression in frontal neocortex was correlated significantly with high expression of endothelial cell markers, dopamine receptor type 2 (DRD2L), and preproenkephalin (PENK) mRNAs, and with worse performance on tasks of verbal fluency. Significant associations were not found between low GABAergic mRNAs and HIV-1 RNA concentration in the brain, the history of cART, or HIV encephalitis. Pathological evidence of neurodegeneration of the affected GABAergic neurons was not present. We conclude that abnormally low expression of GABAergic markers is prevalent in HIV-1 infected patients. Interrelationships with other neurotransmitter systems including dopaminergic transmission and with endothelial cell markers lend added support to suggestions that synaptic plasticity and cerebrovascular anomalies are involved with HAND in virally suppressed patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s11481-016-9652-2) contains supplementary material, which is available to authorized users.

The Etiological Diagnosis and Outcome in Patients of Acute Viral Encephalitis: A Prospective Observational Study at Tertiary Care Centre of North India

Background: Encephalitis, despite being an uncommon entity, is of public health importance worldwide because of its high morbidity and mortality. Around 70% of the disease burden is in Uttar Pradesh itself. Purpose of study: To study the etiological prevalence and outcome of different viruses as causative agent of acute viral encephalitis in patients reporting to a tertiary health care center in North India. Methods: All the patients presenting with febrile encephalopathy attending the medicine outdoor patient department or emergency of medicine department were enrolled in the study, of these a total of 92 patients fulfilling the inclusion criteria were included in the study. An informed consent from the patients/their attendants was obtained. Results: Minimum age of patients was found to be 14 years while maximum age was 61 years. Around 65.22% were males and majority of the patients were from Barabanki (22.83%). Magnetic Resonance Imaging findings were found to be positive in 85.87%. Most common etiology was Japanese encephalitis (38.04%) with human immunodeficiency Virus encephalitis (3.26%) being least common. After a follow up at 1 month, neurological sequelae were found to be highest in Japanese encephalitis while 100% mortality in human immunodeficiency virus encephalitis and recovery was highest in Dengue encephalitis (85.00%). Difference in outcome of different types of encephalitis was found to be statistically significant. Recovery was highest in age group up to 20 years (57.69%). Difference in outcome and age of patients was found to be statistically significant. Conclusion: Early Reporting, appropriate workup and stabilization of the suspected acute viral encephalitis patients are important so as to reduce the morbidity and mortality.

Commentary: Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

Commentary: Methamphetamine mediates immune dysregulation in a murine model of chronic viral infection

Gene Expression in HIV-Associated Neurocognitive Disorders: A Meta-Analysis.

To identify differentially expressed (DE) genes in HIV-associated neurocognitive disorders (HAND) patients in comparison with HIV-infected patients without HAND and controls. A meta-analysis of publicly available gene expression data from HIV postmortem brain tissue studies. We selected studies using clearly defined inclusion and exclusion criteria. Within study data preprocessing and individual analyses were performed for each brain region. The following meta-analytic methods were applied: combining P values, combining effect sizes with and without a permutation method. The DE genes were defined with a false discovery rate less than 5% using Benjamini-Hochberg method. Our meta-analysis on 3 studies encompasses analyses of over 48 postmortem brains [25 HAND, 7 HIV encephalitis (HIVE), 8 HIV-infected patients, and 8 controls]. Overall, 411 genes in white matter were DE in HAND with HIVE patients when comparing with controls. Of these, 94 genes were significantly expressed in all statistical methods. These 94 genes participate in significant pathways such as immune system, interferon response, or antigen presentation. Sixty-six of the 94 genes were significantly upregulated with log2 intensities greater than 2-fold. Strong examples of the highly upregulated genes were PSMB8-AS1, APOL6, TRIM69, PSME1, CTSB, HLA-E, GPNMB, UBE2L6, PSME2, NET1, CAPG, B2M, RPL38, GBP1, and PLSCR1. Only BTN3A2 was expressed in HAND with HIVE patients as compared with HAND patients without HIVE. A number of genes were DE in our meta-analysis that were not identified in the individual analyses. The meta-analytic approach has increased statistical power for identifying DE genes in HAND.

Encefalitis por virus de inmunodeficiencia humana, reporte de un caso y revisión de tema

En este artículo se presenta el caso de un paciente con diagnóstico histológico de encefalitis por virus de inmunodeficiencia humana - (VIH), con múltiples coinfecciones incluyendo oportunistas. Es un caso llamativo, pues claramente la incidencia de dicha enfermedad ha decrecido ostensiblemente en la era post terapia antiretroviral de gran efectividad (TARGA). Es un paciente masculino heterosexual de 63 años con conductas sexuales de riesgo, que ingresó a un hospital de cuarto nivel con síntomas respiratorios y durante su hospitalización se le diagnosticó VIH / SIDA estadio C3, múltiples infecciones tales como: hepatitis B, neurosífilis, criptococosis sistémica, toxoplasmosis cerebral, histoplasmosis cutánea, candidiasis y herpes oral; recibió tratamiento y falleció 27 días después por criptococosis diseminada. Se le practicó autopsia y se observó en sustancia blanca del sistema nervioso central numerosos nódulos microgliales, linfocitos perivascular y células gigantes multinucleadas sin formación de granulomas, característicos de la encefalitis por VIH. Este paciente es un ejemplo de la historia natural por VIH en estadío avanzado con compromiso del sistema nervioso central.

Neurological conditions coursing with personality changes

Background: Diagnosis of most psychiatric disorders is syndromic and cannot be confirmed by laboratory, pathologic examinations. However, neurological conditions require anatomical and physiological precise location of the lesions, through imaging exams, clinical examination, followed by histopathology. When neurological and psychiatric approaches are mutually exclusive, diagnosis and treatment may be compromised. Personality changes are etiologically nonspecific symptoms, common to neurological and psychiatric diseases. Objective: Evaluate neurological causes of personality changes. Materials and methods: A search was performed in Pubmed using “neurology AND psychiatry”. Only the free full texts published in the last 5 years were considered. There were 127 results, of which only 7 approached the subject of interest. A book of neurology was also considered. Results: When patients present with subacute onset personality disorder, neurological lesions should be investigated in bilateral fronto-medial regions, basal ganglia, thalamus, which are the most frequent locations in these conditions. The commonest etiologies are vascular, cranioencephalic trauma (CET), HIV encephalitis, vitamin B12 deficiency. Orbitofrontal and caudate nucleus lesions cause uninhibited behavior, observed in degenerative, vascular diseases, tumors, CET. Irritability, explosive behavior is associated with orbitofrontal bilateral lesions, as in Huntington's disease, stroke, CET. Indifference, stillness, judgment and self-criticism disturbances are common in Pick frontotemporal dementia, and may also occur in advanced Alzheimer's disease. Brain tumors rarely manifest firstly as cognitive or behavioral disorders. Conclusion: The increasing knowledge of brain-mind interaction reinforces the relevance of considering organic diseases when dealing with psychological symptoms, and, therefore, mood/personality disturbances might hide a neurologic condition.

Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure.

We investigated the role of autophagy in HIV-infected subjects with neurocognitive impairment (NCI) ± HIV encephalitis (HIVE), many of which had a history of polysubstance abuse/dependence, using post-mortem brain tissues to determine whether differences in autophagy related factors may be more associated with NCI or NCI-encephalitis. Using qRT-PCR, we detected significant differences in gene expression levels with SQSTM1, LAMP1 higher in HIV-infected subjects without NCI while ATG5, SQSTM1 were then lower in HIV infection/NCI and ATG7, SQSTM1 being higher in NCI-HIVE. Immunohistochemical labeling of these autophagy associated proteins (also including Beclin 1 and LC3B) in Iba1-positive microglial cells showed generally higher immunoreactivity in the NCI and NCI-HIVE groups with more focal vs. diffuse patterns of expression in the NCI-HIVE group. Furthermore, analysis of microarray data from these same subjects found significantly higher levels of LAMP1 in NCI-HIVE compared to uninfected subjects in the basal ganglia. Finally, we tested the effect of supernatant from HIV-1-infected microglia and HIV-1 Tat protein in combination with morphine on neurons in vitro and found opposing events with both significant inhibition of autophagic flux and reduced dendrite length for morphine and supernatant treatment while Tat and morphine exposure resulted in lower autophagic activity at an earlier time point and higher levels in the later. These results suggest autophagy genes and their corresponding proteins may be differentially regulated at the transcriptional, translational, and post-translational levels in the brain during various stages of the HIV disease and that infected individuals exposed to morphine can experience mixed signaling of autophagic activity which could lead to more severe NCI than those without opioid use.