Exploring resting-state EEG oscillations in patients with Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVE: Quantitative resting-state electroencephalography (rs-EEG) is a convenient method for characterizing the functional impairments and adaptations of the brain that has been shown to be valuable for assessing many neurological and psychiatric disorders, especially in monitoring disease status and assisting neuromodulation treatment. However, it has not yet been explored in patients with neuromyelitis optica spectrum disorder (NMOSD). This study aimed to investigate the rs-EEG features of NMOSD patients and explore the rs-EEG features related to disease characteristics and complications (such as anxiety, depression, and fatigue). METHODS: A total of 32 NMOSD patients and 20 healthy controls (HCs) were recruited; their demographic and disease information were collected, and their anxiety, depression, and fatigue symptoms were evaluated. The rs-EEG power spectra of all the participants were obtained. After excluding the participants with low-quality rs-EEG data during processing, statistical analysis was conducted based on the clinical information and rs-EEG data of 29 patients and 19 HCs. The rs-EEG power (the mean spectral energy (MSE) of absolute power and relative power in all frequency bands, as well as the specific power for all electrode sites) of NMOSD patients and HCs was compared. Furthermore, correlation analyses were performed between rs-EEG power and other variables for NMOSD patients (including the disease characteristics and complications). RESULTS: The distribution of the rs-EEG power spectra in NMOSD patients was similar to that in HCs. The dominant alpha-peaks shifted significantly towards a lower frequency for patients when compared to HCs. The delta and theta power was significantly increased in the NMOSD group compared to that in the HC group. The alpha oscillation power was found to be significantly negatively associated with the degree of anxiety (reflected by the anxiety subscore of hospital anxiety and depression scale (HADS)) and the degree of depression (reflected by the depression subscore of HADS). The gamma oscillation power was revealed to be significantly positively correlated with the fatigue severity scale (FSS) score, while further analysis indicated that the electrode sites of almost the whole brain region showing correlations with fatigue. Regarding the disease variables, no statistically significant rs-EEG features were related to the main disease features in NMOSD patients. CONCLUSION: The results of this study suggest that the rs-EEG power spectra of NMOSD patients show increased slow oscillations and are potential biomarkers of widespread white matter microstructural damage in NMOSD. Moreover, this study revealed the rs-EEG features associated with anxiety, depression, and fatigue in NMOSD patients, which might help in the evaluation of these complications and the development of neuromodulation treatment. Quantitative rs-EEG analysis may play an important role in the management of NMOSD patients, and future studies are warranted to more comprehensively understand its application value.

The role of basal ganglia network in neural plasticity in neuromyelitis optica spectrum disorder with myelitis.

OBJECTIVES: To explore the alternation of the brain baseline activity in neuromyelitis optica spectrum disorder (NMOSD) patients after myelitis, and characterize the representation of the neural plasticity process. METHODS: Clinical evaluation and resting-state fMRI were obtained from 20 NMOSD patients with myelitis and 20 healthy controls, matched in gender and age. Resting-state networks (RSNs) were identified through independent component analysis (ICA), and functional connectivity (FC) intra-RSNs and between region-of-interest (ROI) seed to whole-brain voxels were analyzed. Between-group comparisons and correlations with motor performance were also assessed. RESULTS: A total of 14 main functional RSNs were identified. Group comparison of intra-network FCs revealed that FC strengths increased in basal ganglia network (BGN) and left frontoparietal network, decreased in sensorimotor network and default mode network in NMOSD. Better motor performance was found closely correlated with higher FC of BGN. Additionally, remarkably increased FC between caudate in BGN with cerebellum, frontal lobe and parietal lobe was discovered in further ROI-based whole-brain voxels FC analysis. CONCLUSIONS: NMOSD patients presented wide brain resting-state functional connectivity alterations after myelitis, and BGN might be highly active in the process of neural plasticity in chronic stage of NMOSD. Besides, understanding neural plasticity representation, especially that in NMOSD patients after myelitis, might have important applications in monitoring and designing rehabilitative approaches.

Conditional Deletion of PDK1 in the Forebrain Causes Neuron Loss and Increased Apoptosis during Cortical Development.

Decreased expression but increased activity of PDK1 has been observed in neurodegenerative disease. To study in vivo function of PDK1 in neuron survival during cortical development, we generate forebrain-specific PDK1 conditional knockout (cKO) mice. We demonstrate that PDK1 cKO mice display striking neuron loss and increased apoptosis. We report that PDK1 cKO mice exhibit deficits on several behavioral tasks. Moreover, PDK1 cKO mice show decreased activities for Akt and mTOR. These results highlight an essential role of endogenous PDK1 in the maintenance of neuronal survival during cortical development.

Conditional inactivation of Akt three isoforms causes tau hyperphosphorylation in the brain.

BACKGROUND: Tau hyperphosphorylation plays a critical role in neurodegenerative diseases [EMBO Mol Med. 6:1142-60, 2014; Annu Rev Neurosci. 24:1121-59, 2001]. Recent evidence has shown that Akt is down-regulated in AD [J Pathol. 225:54-62, 2011]. However, it remained unknown which pathological process, e.g. tau pathology or neuron death, Akt may contribute to. In this study, Cre-loxP technique was employed to generate a viable Akt three isoforms conditional knockout (Akt cTKO) mouse in which total Akt levels were dramatically reduced in the adult brain. RESULTS: Significantly increased levels of tau phosphorylated (p-tau) at various sites were observed in Akt cTKO mice as compared to age-matched littermate controls. Increased levels for phosphorylated GSK3α and phosphorylated PKA substrates were detected in Akt cTKO brains. In contrast, no significant changes on p-tau levels were found in Akt1(-/-), Akt2(-/-) or Akt3(-/-) mice. CONCLUSIONS: Akt may regulate tau phosphorylation in the adult brain by affecting activities for PKA and GSK3α.

Stability of HIB-Cul3 E3 ligase adaptor HIB Is Regulated by Self-degradation and Availability of Its Substrates.

The HIB-Cul3 complex E3 ligase regulates physiological homeostasis through regulating its substrate stability and its activity can be modulated by changing HIB abundance. However, regulation of HIB remains elusive. Here we provide evidence that HIB is degraded through the proteasome by Cul3-mediated polyubiquitination in K48 manner in Drosophila. Strikingly, HIB is targeted for degradation by itself. We further identify that three degrons ((52)LKSS(56)T, (76)LDEE(80)S and (117)MESQ(121)R) and K185 and K198 of HIB are essential for its auto-degradation. Finally, we demonstrate that HIB-Cul3 substrates, Ci and Puc, can effectively protect HIB from HIB-Cul3-mediated degradation. Taken together, our study indicates that there is an exquisite equilibrium between the adaptor and targets to achieve the tight control of the HIB, which is essential for maintaining suitable Hh and JNK signaling. And the mechanism of adaptor self-degradation and reciprocal control of the abundance between adaptor and its substrates is also applied to BTB-Cul3 E3 ligase adaptor dKeap1, dDiablo and dKLHL18.

Minocycline reduces neuroinflammation but does not ameliorate neuron loss in a mouse model of neurodegeneration.

Minocycline is a broad-spectrum tetracycline antibiotic. A number of preclinical studies have shown that minocycline exhibits neuroprotective effects in various animal models of neurological diseases. However, it remained unknown whether minocycline is effective to prevent neuron loss. To systematically evaluate its effects, minocycline was used to treat Dicer conditional knockout (cKO) mice which display age-related neuron loss. The drug was given to mutant mice prior to the occurrence of neuroinflammation and neurodegeneration, and the treatment had lasted 2 months. Levels of inflammation markers, including glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule1 (Iba1) and interleukin6 (IL6), were significantly reduced in minocycline-treated Dicer cKO mice. In contrast, levels of neuronal markers and the total number of apoptotic cells in Dicer cKO mice were not affected by the drug. In summary, inhibition of neuroinflammation by minocycline is insufficient to prevent neuron loss and apoptosis.

Age-dependent neuron loss is associated with impaired adult neurogenesis in forebrain neuron-specific Dicer conditional knockout mice.

Impairment in the microRNA (miRNA) network causes a number of neurodegenerative diseases. Endoribonuclease Dicer is a key RNase to produce mature miRNAs. It has been shown that Dicer is important for the maintenance of excitatory neuron survival during early postnatal period. However, the role of Dicer in adult mature excitatory neuron survival is not clear. In this study, we generated a mouse model in which Dicer is conditionally inactivated in forebrain excitatory neurons from a mature stage, and this line is termed Dicer conditional knockout (cKO). Significant age-dependent neurodegeneration was observed in the cortex of Dicer cKO mice, indicating an important role of Dicer in the maintenance of mature excitatory neuron survival in the adult cortex. Impairment in adult neurogenesis was found in 6-month but not in young Dicer cKO mice. However, astrocytosis was detected in young Dicer cKO mice displaying no apparent neuron loss. Overall, neurogenesis impairment and neuroinflammation may play pivotal roles in the progression of neurodegeneration.