Aberrant miR-339-5p/neuronatin signaling causes prodromal neuronal calcium dyshomeostasis in mutant presenilin mice.

Mushroom spine loss and calcium dyshomeostasis are early hallmark events of age-related neurodegeneration, such as Alzheimer's disease (AD), that are connected with neuronal hyperactivity in early pathology of cognitive brain areas. However, it remains elusive how these key events are triggered at the molecular level for the neuronal abnormality that occurs at the initial stage of disease. Here, we identify downregulated miR-339-5p and its upregulated target protein, neuronatin (Nnat), in cortex neurons from the presenilin-1 M146V knockin (PSEN1-M146V KI) mouse model of familial AD (FAD). Inhibition of miR-339-5p or overexpression of Nnat recapitulates spine loss and endoplasmic reticulum calcium overload in cortical neurons with the PSEN1 mutation. Conversely, either overexpression of miR-339-5p or knockdown of Nnat restores spine morphogenesis and calcium homeostasis. We used fiber photometry recording during the object-cognitive process to further demonstrate that the PSEN1 mutant causes defective habituation in neuronal reaction in the retrosplenial cortex and that this can be rescued by restoring the miR-339-5p/Nnat pathway. Our findings thus reveal crucial roles of the miR-339-5p/Nnat pathway in FAD that may serve as potential diagnostic and therapeutic targets for early pathogenesis.

Mechanisms of motor symptom improvement by long-term Tai Chi training in Parkinson's disease patients.

BACKGROUND: Tai Chi has been shown to improve motor symptoms in Parkinson's disease (PD), but its long-term effects and the related mechanisms remain to be elucidated. In this study, we investigated the effects of long-term Tai Chi training on motor symptoms in PD and the underlying mechanisms. METHODS: Ninety-five early-stage PD patients were enrolled and randomly divided into Tai Chi (n = 32), brisk walking (n = 31) and no-exercise (n = 32) groups. At baseline, 6 months and 12 months during one-year intervention, all participants underwent motor symptom evaluation by Berg balance scale (BBS), Unified PD rating-scale (UPDRS), Timed Up and Go test (TUG) and 3D gait analysis, functional magnetic resonance imaging (fMRI), plasma cytokine and metabolomics analysis, and blood Huntingtin interaction protein 2 (HIP2) mRNA level analysis. Longitudinal self-changes were calculated using repeated measures ANOVA. GEE (generalized estimating equations) was used to assess factors associated with the longitudinal data of rating scales. Switch rates were used for fMRI analysis. False discovery rate correction was used for multiple correction. RESULTS: Participants in the Tai Chi group had better performance in BBS, UPDRS, TUG and step width. Besides, Tai Chi was advantageous over brisk walking in improving BBS and step width. The improved BBS was correlated with enhanced visual network function and downregulation of interleukin-1ß. The improvements in UPDRS were associated with enhanced default mode network function, decreased L-malic acid and 3-phosphoglyceric acid, and increased adenosine and HIP2 mRNA levels. In addition, arginine biosynthesis, urea cycle, tricarboxylic acid cycle and beta oxidation of very-long-chain fatty acids were also improved by Tai Chi training. CONCLUSIONS: Long-term Tai Chi training improves motor function, especially gait and balance, in PD. The underlying mechanisms may include enhanced brain network function, reduced inflammation, improved amino acid metabolism, energy metabolism and neurotransmitter metabolism, and decreased vulnerability to dopaminergic degeneration. Trial registration This study has been registered at Chinese Clinical Trial Registry (Registration number: ChiCTR2000036036; Registration date: August 22, 2020).

Altered structural and functional connectivity in CSF1R-related leukoencephalopathy.

CSF1R-related leukoencephalopathy is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few studies have investigated the intrinsic brain alternations of patients with CSF1R-related leukoencephalopathy. We aim to evaluate the structural and functional changes in those patients. Seven patients with CSF1R-related leukoencephalopathy and 15 age-matched healthy controls (HCs) underwent multimodal magnetic resonance imaging (MRI), including high-resolution T1-weighted imaging, T2-weighted fluid attenuated inversion recovery imaging, diffusion-weighted imaging, diffusion kurtosis imaging (DKI) and resting-state functional MRI. First, to detect structural alterations, the gray matter volumes were compared using voxel-based morphometry analyses. Second, DKI parametric maps were used to evaluate the white matter (WM) connectivity changes. Finally, we constructed a seed-based resting-state functional connectivity matrix based on 90 regions of interest and examined the functional network changes of CSF1R-related leukoencephalopathy. Unlike the HCs, patients with CSF1R-related leukoencephalopathy predominantly had morphological atrophy in the bilateral thalamus and left hippocampus. In addition, the abnormal diffusivity was mainly distributed in the splenium of the corpus callosum, periventricular regions, centrum semiovale, subcortical U-fibers and midline cortex structures. Moreover, the patients had significantly reduced functional connectivity between the bilateral caudate nucleus and their contralateral hippocampus. Therefore, in addition to hyperintensity on the T2-weighted images, CSF1R-related leukoencephalopathy also showed abnormal structural and functional alterations, including subcortical atrophy and reduced functional connectivity, as well as altered diffuse parameters in the WM and subcortical regions. These findings expand our understanding of the potential pathophysiologic mechanism behind this hereditary disease.

Computerized cognitive training for Chinese mild cognitive impairment patients: A neuropsychological and fMRI study.

BACKGROUND: Computerized multi-model training has been widely studied for its effect on delaying cognitive decline. In this study, we designed the first Chinese-version computer-based multi-model cognitive training for mild cognitive impairment (MCI) patients. Neuropsychological effects and neural activity changes assessed by functional MRI were both evaluated. METHOD: MCI patients in the training group were asked to take training 3-4 times per week for 6 months. Neuropsychological and resting-state fMRI assessment were performed at baseline and at 6 months. Patients in both groups were continuously followed up for another 12 months and assessed by neuropsychological tests again. RESULTS: 78 patients in the training group and 63 patients in the control group accomplished 6-month follow-up. Training group improved 0.23 standard deviation (SD) of mini-mental state examination, while control group had 0.5 SD decline. Addenbrooke's cognitive examination-revised scores in attention (p = 0.002) and memory (p = 0.006), as well as stroop color-word test interference index (p = 0.038) and complex figure test-copy score (p = 0.035) were also in favor of the training effect. Difference between the changes of two groups after training was not statistically significant. The fMRI showed increased regional activity at bilateral temporal poles, insular cortices and hippocampus. However, difference between the changes of two groups after another 12 months was not statistically significant. CONCLUSIONS: Multi-model cognitive training help MCI patients to gained cognition benefit, especially in memory, attention and executive function. Functional neuroimaging provided consistent neural activation evidence. Nevertheless, after one-year follow up after last training, training effects were not significant. The study provided new evidence of beneficial effect of multi-model cognitive training.

N1 and P1 Components Associate With Visuospatial-Executive and Language Functions in Normosmic Parkinson's Disease: An Event-Related Potential Study.

Background: Hyposmia is one of the most important clinical markers of Parkinson's disease (PD) with a prevalence ranging from 50 to 96% of PD patients. A significant association was found between hyposmia and cognitive impairment of PD. However, there were no reports of event-related potentials (ERP) performance in PD patients with and without hyposmia for cognitive functions assessment. Purpose: The aim of our study was to compare ERP performance and its association with cognitive domains between PD with and without hyposmia. Methods: Olfactory functions were assessed by Sniffin' Sticks test-16 (SS-16). Twenty-four subjects were included in PD with hyposmia group and nineteen were in PD without hyposmia group. ERP measures were recorded during a delayed match to sample (DMS) task with Chinese characters. The parameters of ERP components including N1, N2, P1, P2, and P3 in retrieval epoch were compared between the two groups and the correlation between ERP results and MOCA item score was also analyzed. Results: No significant difference was found in ERP performance between PD with and without hyposmia. Among all participants, N1 latency was significantly negatively related to visuospatial-executive item score of Montreal Cognitive Assessment (MOCA) (r s = -0.381, P = 0.012) and P1 amplitude was positively associated with language item score of MOCA (r s = 0.302, P = 0.049). Within the normosmic group, a significant association was found between N1 latency and visuospatial-executive item score (r s = -0.619, P = 0.005) and there was also a correlation between language score and P1 amplitude (r s = 0.537, P = 0.018). In the hyposmic group, only a significant correlation was found between N1 latency and clock drawing test performance (r s = -0.413, P = 0.045) rather than visuospatial-executive item score. Furthermore, SS-16 score was not found to be significantly associated with either visuospatial-executive or language item score of MOCA. Conclusion: No significant difference was found in ERP components between PD with and without hyposmia. N1 latency and P1 amplitude were respectively associated with visuospatial-executive and language functions in the normosmic group while in the hyposmic group, only a significant correlation was found between N1 latency and clock drawing test performance rather than visuospatial-executive item score in MOCA.

The role of cognitive activity in cognition protection: from Bedside to Bench.

BACKGROUND: Cognitive decline poses a great concern to elderly people and their families. In addition to pharmacological therapies, several varieties of nonpharmacological intervention have been developed. Most training trials proved that a well-organized task is clinically effective in cognition improvement. MAIN BODY: We will first review clinical trials of cognitive training for healthy elders, MCI and AD patients, respectively. Besides, potential neuroprotective and compensatory mechanisms in animal models of AD are discussed. Despite controversy, cognitive training has promising effect on cognitive ability. In animal model of AD, environmental enrichment showed beneficial effect for cognitive ability, as well as neuronal plasticity. Neurotrophin, neurotransmitter and neuromodulator signaling pathway were also involved in the process. Well-designed cognitive activity could benefit cognitive function, and thus life quality of patients and their families. CONCLUSION: The positive effects of cognitive activity is closely related with neural plasticity, neurotrophin, neurotransmitter and neuromodulator signaling pathway changes.

Retrieval Deficiency in Brain Activity of Working Memory in Amnesic Mild Cognitive Impairment Patients: A Brain Event-Related Potentials Study.

In the early stage of Alzheimer disease (AD) or mild cognitive impairment (MCI), working memory (WM) deficiency is prominent and could be attributed to failure in encoding, maintenance or retrieval of information. However, evidence for a retention or retrieval deficit remains equivocal. It is also unclear what cognitive mechanism in WM is impaired in MCI or early AD. We enrolled 46 subjects from our Memory Clinics and community, with 24 amnesic MCI patients and 22 normal subjects. After neurological and cognitive assessments, they performed a classic delayed match to sample (DMS) task with simultaneous event-related potential (ERP) recorded. The ERPs in encoding and retrieval epoch during WM were analyzed separately. The latency and amplitude of every ERP component were compared between two groups, and then analyzed to explore their relationship with neuropsychological performance. Finally, the locations of maximal difference in cortex were calculated by standard low-resolution tomographic analysis. A total of five components were found: P1, N1, P2, N2, and P300. The amplitude of P2 and P300 was larger in normal subjects than in MCI patients only during retrieval, not encoding epoch, while the latency did not show statistical difference. The latency and amplitude of P1 and N1 were similar in two groups. P2 amplitude in the retrieval epoch positively correlated with memory test (auditory verbal learning test) and visual spatial score of Chinese Addenbrooke's Cognitive Examination-Revised (ACE-R), while P300 amplitude correlated with ACE-R. The activation difference in P2 time range was maximal at medial frontal gyrus. However, the difference in cortex activation during P300 time range did not show significance. The amplitude of P2 indicated deficiency in memory retrieval process, potentially due to dysfunction of central executive in WM model. Regarding the location of P2 during WM task, medial frontal plays important role in memory retrieval. The findings in the present study suggested that MCI patients have retrieval deficit, probably due to central executive based on medial frontal gyrus. Thus, it may provide new biomarker for early detection and intervention for aMCI.

Exercise-Related Changes of Networks in Aging and Mild Cognitive Impairment Brain.

Aging and mild cognitive impairment (MCI) are accompanied by decline of cognitive functions. Meanwhile, the most common form of dementia is Alzheimer's disease (AD), which is characterized by loss of memory and other intellectual abilities serious to make difficulties for patients in their daily life. MCI is a transition period between normal aging and dementia, which has been used for early detection of emerging dementia. It converts to dementia with an annual rate of 5-15% as compared to normal aging with 1% rate. Small decreases in the conversion rate of MCI to AD might significantly reduce the prevalence of dementia. Thus, it is important to intervene at the preclinical stage. Since there are still no effective drugs to treat AD, non-drug intervention is crucial for the prevention and treatment of cognitive decline in aging and MCI populations. Previous studies have found some cognitive brain networks disrupted in aging and MCI population, and physical exercise (PE) could effectively remediate the function of these brain networks. Understanding the exercise-related mechanisms is crucial to design efficient and effective PE programs for treatment/intervention of cognitive decline. In this review, we provide an overview of the neuroimaging studies on physical training in normal aging and MCI to identify the potential mechanisms underlying current physical training procedures. Studies of functional magnetic resonance imaging, electroencephalography, magnetoencephalography and positron emission tomography on brain networks were all included. Based on our review, the default mode network, fronto-parietal network and fronto-executive network are probably the three most valuable targets for efficiency evaluation of interventions.

Mental Training for Cognitive Improvement in Elderly People: What have We Learned from Clinical and Neurophysiologic Studies?

Cognitive impairment is a major concern in elderly people, and a variety of nonpharmacological therapies (NPTs) have been developed to help with cognitive decline. One of the most popular therapies is cognitive training, which includes pencil-and-paper puzzles, computerized games, or the combination of the two. Training is designed to have participants perform diverse exercises in one or more cognitive domains. Most clinical training trials indicate that well-organized tasks are clinically effective for cognitive improvement. Neural plasticity is a probable explanation for positive training effects. EEG and fMRI research show that the electrical activity and metabolism of specific brain areas are changed, and these changes are retained for a long period after training. Studies on mice to uncover the cellular and molecular changes underlying neural connectivity have found effective changes in brain networks after learning or training. Rac1 and NMDA receptors are thought to be involved in hippocampal neurogenesis, which is induced by learning. Here we review clinical trials of cognitive training, published during the last five years, and summarized some important characteristics of training tasks design. The probable role of neuronal plasticity and molecular mechanisms in training effects also are discussed. Most importantly, we discuss key ways to modifying the design of tasks based on studies we review. This review mainly identifies and discusses the reasons for positive training effects on cognition from clinical and neurophysiological perspectives. Based on the findings and their related mechanisms, further studies should design more effective and specific training tasks.

Potential Similarities in Temporal Lobe Epilepsy and Alzheimer's Disease: From Clinic to Pathology.

Alzheimer's disease (AD) is clinically characterized by insidious onset of memory and cognitive impairments, which are also presented in patients with temporal lobe epilepsy (TLE). Many studies have shown that seizures occur in some patients with AD, and AD is a risk factor for epilepsy, mainly complex partial and secondary generalized seizure. Here, we focus on the relationship between TLE and AD in clinical and pathological aspects, as they are having similar comorbidities and mechanisms. In this study, we first reviewed the clinical observations that showed concomitant AD and TLE. Then, we picked up common genetic and pathological changes in both the diseases from neurobiological researches. Although both the diseases have delicate differences in many aspects, their common characteristics intrigue more detailed research to be done by newer technology.

[Distribution and regulation of Panx1 protein].

Pannexin1 (Panx1) is a subtype of the newly discovered gap junction proteins named Pannexin(s). Panx1 is widely expressed in the nervous system, cardiovascular system, etc and can form non-selective and large conductance hemichannel. It has been demonstrated that various conditions can regulate Panx1 open and affect the body's physiological function via macromolecular substance (for instance, ATP) releasing. This review gives a detailed introduction to the main distribution of Panxl, summarizes the open and inhibition condition of Panx1, and finally, prospects directions of future research.