Benchawanna Soontornniyomkij

Cerebral β-amyloid deposition predicts HIV-associated neurocognitive disorders in APOE ε4 carriers

Objective:The apolipoprotein E (APOE) &egr;4 allele enhances cerebral accumulation of &bgr;-amyloid (A&bgr;) and is a major risk factor for sporadic Alzheimers disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE &egr;4 genotype and cerebral A&bgr; deposition. Design:Clinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium. Methods:We used multivariable logistic regressions to model outcomes [A&bgr; plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE &egr;4 (allelic discrimination assay), older age (≥50 years), A&bgr; plaques, and their two-way interactions] and comorbid factors. Results:Isocortical A&bgr; deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE &egr;4 and older age were independently associated with the presence of A&bgr; plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 − 35.76 and 1.91−17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of A&bgr; plaques among APOE &egr;4 carriers (adjusted OR 30.00, 95% CI 1.41−638.63, P = 0.029, n = 15), but not in non-&egr;4 carriers (n = 57). Conclusion:The APOE &egr;4 and older age increased the likelihood of cerebral A&bgr; plaque deposition in HIV-infected adults. Generally, A&bgr; plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimers disease brains. Nonetheless, A&bgr; plaques were associated with HAND among APOE &egr;4 carriers. The detection of APOE &egr;4 genotype and cerebral A&bgr; deposition biomarkers may be useful in identifying living HAND patients who could benefit from A&bgr;-targeted therapies.

HIV protease inhibitor exposure predicts cerebral small vessel disease

Objective:HIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND. Design:Clinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network. Methods:We employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection. Results:We found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03–7.9) and 2.6 (95% CI 1.03–6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6–70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1–21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age. Conclusion:Protease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.

Short-term recognition memory impairment is associated with decreased expression of FK506 binding protein 51 in the aged mouse brain

Evidence suggests that increased glucocorticoid receptor (GR) signaling may contribute to cognitive decline with age. We hypothesized that alterations in GR signaling pathway molecules, FK506 binding protein (FKBP) 51 and FKBP52, were associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice, and employed quantitative immunohistochemistry to assess cellular expression of those three proteins in the frontal cortex, hippocampal CA1, and dentate gyrus. Values of the discrimination ratio (DR, a measure of novelty preference) in aged mice were significantly lower than those in young mice (mean 0.54 vs. 0.67, p = 0.003, t test). Aged mice with DR below 0.54 were considered impaired (n = 9). In the three neuroanatomic regions studied, the immunoreactivity normalized to the area measured (IRn) for GR was significantly increased in aged mice regardless of their task performance compared to young mice (p < 0.005), as was the FKBP52 IRn (p < 0.007, U test). In the frontal cortex and CA1, the FKBP51 IRn was significantly lower in impaired aged mice than in unimpaired aged mice (p < 0.01 and <0.05, respectively) and in young mice (p < 0.05 and <0.01, respectively, Dunn’s post hoc test). In aged mice, the frontal cortex FKBP51 IRn correlated directly with DR (rs = 0.68, p = 0.002, Spearman rank correlation). These observations suggest that recognition memory impairment in aged mice is associated with decreased FKBP51 expression that may promote GR-mediated glucocorticoid signaling to a greater extent than in unimpaired aged mice.

Tyrosine kinase B protein expression is reduced in the cerebellum of patients with bipolar disorder

BACKGROUND The role of the cerebellum in coordinating mental activity is supported by its connections with cerebral regions involved in cognitive/affective functioning, with decreased activities on functional neuroimaging observed in the cerebellum of schizophrenia patients performing mental tasks. Brain-derived neurotrophic factor (BDNF)-induced activation of tyrosine kinase B (TrkB) is essential to synaptic plasticity. We hypothesized that alterations in BDNF and TrkB expression in the cerebellum were associated with schizophrenia and affective disorders. METHODS We employed immunohistochemistry and immunoblotting to quantify protein expression of BDNF and TrkB in the cerebellum of patients with schizophrenia, bipolar disorder, and major depression compared to controls (n=15 each). RESULTS While TrkB immunoreactivity in each of the molecular and granule-cell layers was reduced in all 3 disease groups (12-34%) compared to the control (P=0.018 and 0.038, respectively, ANOVA), only the reduction in bipolar disorder remained statistically significant upon Tukey-Kramer post hoc analyses (P=0.019 and 0.021, respectively). Apparent decreases in BDNF immunoreactivity in all 3 disease groups (12-30%) compared to the control were not statistically significant. TrkB immunoreactivity was not significantly associated with any of the demographic, clinical, and postmortem variables. Immunoblotting displayed an 85-kDa TrkB-immunoreactive band, consistent with a truncated isoform, in all 60 cases. LIMITATIONS On immunoblotting, apparent decreases in 85-kDa-TrkB levels in all 3 disease groups compared to the control were not statistically significant. CONCLUSIONS Our finding of reduced TrkB expression in bipolar disorder suggests that dysregulation of TrkB-mediated neurotrophin signaling in the cerebellum may play a role in the pathophysiology of this disease.

Hippocampal calbindin-1 immunoreactivity correlate of recognition memory performance in aged mice

Aging-related dysregulation of neuronal calcium metabolism, which not only involves the control of calcium fluxes but also the cytosolic calcium buffering system such as calbindin-1 (Calb1), may disturb synaptic plasticity and thereby memory functioning. Calb1 expression has been shown to affect hippocampal long-term potentiation and learning and to play a neuroprotective role in animal models of ischemic brain injury and neurodegenerative disorders. We hypothesize that memory performance in aged mice correlates with neuronal Calb1 protein expression in the hippocampal formation. We studied a set of 18 aged and 22 young male C57BL/6N mice, in which the aged group performed poorer than the young in single-trial novel object recognition testing (two-tailed p=0.005, U test). Apparent decreases in the Calb1 immunoreactivity (measured by quantitative immunohistochemistry) in aged mice compared to that in young mice were not statistically significant either in the hippocampal CA1 subfield or dentate gyrus. In the aged mouse group, levels of Calb1 immunoreactivity both in the CA1 subfield and dentate gyrus correlated directly with the measure of recognition memory performance (Spearman rank correlation r(s)=0.47 and 0.48, two-tailed p=0.047 and 0.044, respectively). Our results suggest that hippocampal Calb1 expression affects memory performance in aged mice probably via its role in maintaining neuronal calcium homeostasis. Alternatively, our finding of lower Calb1 immunoreactivity with poorer memory performance in aged mice might be attributed to saturation of Calb1 protein by higher levels of intracellular calcium, due to aging-related dysregulation of neuronal calcium fluxes.

Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice

Constitutive macroautophagy involved in the turnover of defective long-lived proteins and organelles is crucial for neuronal homeostasis. We hypothesized that macroautophagic dysregulation in selective brain regions was associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice and employed immunohistochemistry to assess cellular distribution of proteins involved in the selective degradation of ubiquitinated proteins via macroautophagy. Values of the discrimination ratio (DR, a measure of short-term recognition memory performance) in aged mice were significantly lower than those in young mice (median, 0.54 vs. 0.67; p = 0.005, U test). Almost exclusively in aged mice, there were clusters of puncta immunoreactive for microtubule-associated protein 1 light chain 3 (LC3), ubiquitin- and LC3-binding protein p62, and ubiquitin in neuronal processes predominantly in the hippocampal formation, olfactory bulb/tubercle, and cerebellar cortex. The hippocampal burden of clustered puncta immunoreactive for LC3 and p62 exhibited inverse linear correlations with DR in aged mice (ρ = −0.48 and −0.55, p = 0.044 and 0.018, respectively, Spearman’s rank correlation). These findings suggest that increased accumulation of autophagosomes within neuronal processes in selective brain regions is characteristic of aging. The dysregulation of macroautophagy can adversely affect the turnover of aggregate-prone proteins and defective organelles, which may contribute to memory impairment in aged mice.

Abnormalities in chemokine levels in schizophrenia and their clinical correlates.

Chemokines are promising biomarkers of immune activation and inflammation, but evidence for chemokine abnormalities in schizophrenia and their relationship to clinical factors remains inconclusive. We aimed to understand chemokine-related diagnostic differences and clinical correlates using a comprehensive panel and studying a large, well-characterized sample of adults with and without schizophrenia. We studied 134 outpatients with schizophrenia or schizoaffective disorder and 112 healthy comparison (HC) individuals, 26 to 65years of age. Clinical measures were obtained, and plasma levels of 11 chemokines were assessed using multiplex immunoassay. Schizophrenia vs. HC differences were tested for each chemokine, adjusting for age, gender, body mass index, and current smoking status. We also examined whether age and gender relationships differed between diagnostic groups. Using logistic regression, we created a Chemokine Index (CI) and explored its clinical correlates. Levels of monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1β (MIP-1β/CCL4), Eotaxin-1 (CCL11), thymus and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22) were significantly higher in persons with schizophrenia than HCs. Group differences in TARC were reduced after adjusting for covariates. The CI, a linear combination of Eotaxin-1 and MDC levels, was positively associated with age, duration of schizophrenia, and severity of negative symptoms. Levels of chemokines with neuroimmune regulatory effects were higher in individuals with schizophrenia, particularly in older and chronic patients. Treatments aimed at normalizing chemokine levels might improve mental and physical health among schizophrenia patients as they age.

Modulation of BK Channel by MicroRNA-9 in Neurons After Exposure to HIV and Methamphetamine

MicroRNAs (miR) regulate phenotype and function of neurons by binding to miR-response elements (MRE) in the 3′ untranslated regions (3′UTR) of various messenger RNAs to inhibit translation. MiR expression can be induced or inhibited by environmental factors like drug exposure and viral infection, leading to changes in cellular physiology. We hypothesized that the effects of methamphetamine (MA) and human immunodeficiency virus (HIV)-infection in the brain will induce changes in miR expression, and have downstream regulatory consequences in neurons. We first used a PCR-based array to screen for differential expression of 380 miRs in frontal cortex autopsy tissues of HIV-positive MA abusers and matched controls. These results showed significantly increased expression of the neuron-specific miR-9. In vitro, we used SH-SY5Y cells, an experimental system for dopaminergic studies, to determine miR expression by quantitative PCR after exposure to MA in the presence or absence of conditioned media from HIV-infected macrophages. Again, we found that miR-9 was significantly increased compared to controls. We also examined the inwardly rectifying potassium channel, KCNMA1, which has alternative splice variants that contain an MRE to miR-9. We identified alternate 3′UTRs of KCNMA1 both in vitro and in the autopsy specimens and found differential splice variant expression of KCNMA1, operating via the increased miR-9. Our results suggest that HIV and MA -induced elevated miR-9, leading to suppression of MRE-containing splice variants of KCNMA1, which may affect neurotransmitter release in dopaminergic neurons.

Antioxidant sestrin-2 redistribution to neuronal soma in human immunodeficiency virus-associated neurocognitive disorders

Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer’s disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronal-soma predominance (S; P < 0.0001, Chi-square test for linear trend). Among HIV cases showing the NS or S pattern, HAND cases were preferentially associated with the S pattern (n = 10 of 20) compared to cognitively intact cases (n = 1 of 11; P = 0.047, Fisher’s exact test). In AD brains, sestrin-2 immunoreactivity was mostly intense in the neuropil and co-localized with phospho-Tau immunoreactivity in a subset of neurofibrillary lesions. Phospho-Tau-immunoreactive neurofibrillary lesions were rare in HIV cases and their occurrence was not associated with HAND. Levels of isocortical 8-hydroxy-deoxyguanosine (marker of nucleic acid oxidation) immunoreactivity were not significantly altered in HAND cases compared to cognitively intact HIV cases. In conclusion, the sestrin-2 immunoreactivity redistribution to neuronal soma in HAND suggests unique involvement of sestrin-2 in the pathophysiology of HAND, which is different from the role of sestrin-2 in AD pathogenesis. Alternatively, the difference in sestrin-2 immunoreactivity distribution between HAND and AD may be related to different degrees of severity or stages of oxidative stress.

Peripheral inflammation related to lower fMRI activation during a working memory task and resting functional connectivity among older adults: a preliminary study.

Peripheral inflammation has been associated with adverse effects on cognition and brain structure in late life, a process called ‘inflammaging.’ Identifying biomarkers of preclinical cognitive decline is critical in the development of preventative therapies, and peripheral inflammation may be able to serve as an indicator of cognitive decline. However, little is known regarding the relationship between peripheral inflammation and brain structure and function among older adults.