Current Understanding on Psilocybin for Major Depressive Disorder: A Review Focusing on Clinical Trials.

Previous studies suggested effectiveness of psilocybin in the field of mental health. FDA designated psilocybin as a "breakthrough therapy" for the treatment of treatment-resistant depression (TRD) in 2018. This paper provided a review of psilocybin's potential role in treatment of depression by focusing on published clinical trials. Studies showed that psilocybin, an agonist on 5-HT2A receptors, manifests antidepressant and anxiolytic effects by increasing glutamate transmission, reducing brain inflammation, decreasing default mode network activity. In terms of clinical trials, eleven studies (six open-label and five double blinded randomized clinical trials [DB-RCTs]) trials exploring psilocybin's impact on depression were found. Among open-label studies, a pilot study on TRD patients demonstrated significant reductions in depressive symptoms after two psilocybin sessions. Psilocybin also improved cognitive bias associated with depression. Extension studies confirmed sustained improvements and high remission rates. Among five DB-RCTs, two showed that psilocybin led to significant reductions in anxiety and depression in cancer patients, and the improvements sustained for over six months. In MDD, psilocybin showed rapid reductions in depression, with higher remission rates compared to escitalopram in a DB-RCT. Another DB-RCT showed that psilocybin induced higher decrease in depression around 6 hours after their administrations than placebo. The last DB-RCT showed that in patients with TRD, a single dose of psilocybin 25 mg, but not psilocybin 10 mg, resulted in superior antidepressant effect than psilocybin 1 mg. Overall, psilocybin showed promise in treating depression and anxiety, with notable safety profiles. Further research should explore optimal dosages and long-term effects.

Neuroplastic and Pro-cognitive Effects of Granulocyte Colony Stimulating Factor in Healthy Adults: A Pilot Study.

OBJECTIVE: Granulocyte colony-stimulating factor (G-CSF) is a growth factor used to regulate the mobilization of bone marrow progenitor cells and has been shown to promote brain repair and reduce inflammation. This study aimed to investigate the pro-cognitive and neuroplastic effects of G-CSF in healthy adults. METHODS: Sixteen healthy adults or donors of hematopoietic stem cell transplantation received G-CSF injections for 5 consecutive days, and their blood samples were collected before, immediately after, and 3 weeks after the G-CSF injections. Twelve subjects underwent neuropsychological testing before and 12 weeks after the G-CSF injections. RESULTS: The study found that G-CSF administration resulted in significant improvements in cognitive function, as measured by the Rey- Osterrieth Complex Figure test for immediate recall, delayed recall, and recognition score at 12 weeks after the injections. The blood levels of brain-derived neurotrophic factor, interleukin-4, and interleukin-8 were significantly increased immediately after the injections and returned to baseline levels after 3 weeks. There was no significant change in the plasma level of Multimer Detection System-oligomerized amyloid beta. CONCLUSION: Our results might suggest that G-CSF has neuroplastic and pro-cognitive effects in healthy adults. However, further study containing a larger sample size is needed to confirm our findings.

Olfactory Dysfunction Is Associated with Cerebral Amyloid Deposition and Cognitive Function in the Trajectory of Alzheimer's Disease.

Olfactory dysfunction is consistently observed in individuals with Alzheimer's disease (AD), but its association with beta-amyloid (Aß) deposition remains unclear. This study aimed to investigate the relationship among olfactory function, cerebral Aß deposition, and neuropsychological profiles in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. A total of 164 participants were included, and olfactory function was assessed using the brief smell identification test (B-SIT). Cerebral Aß deposition was measured using [18F]-flutemetamol PET imaging (A-PET). The results show a significant group difference in olfactory function, with the highest impairment observed in the Aß-positive MCI and AD dementia groups, and the impairment was the lowest in Aß-negative NCI. Olfactory dysfunction was positively associated with cognitive impairments across multiple domains. Furthermore, individuals with Aß deposition had lower olfactory function compared to those without Aß, even within the same neuropsychological stage. The association between olfactory dysfunction and Aß deposition was observed globally and in specific cortical regions. These findings suggest that olfactory dysfunction is associated with both cognitive function and cerebral Aß pathology in the trajectory of AD. Olfactory deficits may serve as an additional marker for disease progression and contribute to understanding the underlying mechanisms of AD.

Development of Amyloid PET Analysis Pipeline Using Deep Learning-Based Brain MRI Segmentation-A Comparative Validation Study.

Amyloid positron emission tomography (PET) scan is clinically essential for the non-invasive assessment of the presence and spatial distribution of amyloid-beta deposition in subjects with cognitive impairment suspected to have been a result of Alzheimer's disease. Quantitative assessment can enhance the interpretation reliability of PET scan; however, its clinical application has been limited due to the complexity of preprocessing. This study introduces a novel deep-learning-based approach for SUVR quantification that simplifies the preprocessing step and significantly reduces the analysis time. Using two heterogeneous amyloid ligands, our proposed method successfully distinguished standardized uptake value ratio (SUVR) between amyloidosis-positive and negative groups. The proposed method's intra-class correlation coefficients were 0.97 and 0.99 against PETSurfer and PMOD, respectively. The difference of global SUVRs between the proposed method and PETSurfer or PMOD were 0.04 and -0.02, which are clinically acceptable. The AUC-ROC exceeded 0.95 for three tools in the amyloid positive assessment. Moreover, the proposed method had the fastest processing time and had a low registration failure rate (1%). In conclusion, our proposed method calculates SUVR that is consistent with PETSurfer and PMOD, and has advantages of fast processing time and low registration failure rate. Therefore, PET quantification provided by our proposed method can be used in clinical practice.

Hypermethylation of Mest promoter causes aberrant Wnt signaling in patients with Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to dementia and behavioral changes. Extracellular deposition of amyloid plaques (Aß) and intracellular deposition of neurofibrillary tangles in neurons are the major pathogenicities of AD. However, drugs targeting these therapeutic targets are not effective. Therefore, novel targets for the treatment of AD urgently need to be identified. Expression of the mesoderm-specific transcript (Mest) is regulated by genomic imprinting, where only the paternal allele is active for transcription. We identified hypermethylation on the Mest promoter, which led to a reduction in Mest mRNA levels and activation of Wnt signaling in brain tissues of AD patients. Mest knockout (KO) using the CRIPSR/Cas9 system in mouse embryonic stem cells and P19 embryonic carcinoma cells leads to neuronal differentiation arrest. Depletion of Mest in primary hippocampal neurons via lentivirus expressing shMest or inducible KO system causes neurodegeneration. Notably, depletion of Mest in primary cortical neurons of rats leads to tau phosphorylation at the S199 and T231 sites. Overall, our data suggest that hypermethylation of the Mest promoter may cause or facilitate the progression of AD.

Potential application of human neural crest-derived nasal turbinate stem cells for the treatment of neuropathology and impaired cognition in models of Alzheimer's disease.

BACKGROUND: Stem cell transplantation is a fascinating therapeutic approach for the treatment of many neurodegenerative disorders; however, clinical trials using stem cells have not been as effective as expected based on preclinical studies. The aim of this study is to validate the hypothesis that human neural crest-derived nasal turbinate stem cells (hNTSCs) are a clinically promising therapeutic source of adult stem cells for the treatment of Alzheimer's disease (AD). METHODS: hNTSCs were evaluated in comparison with human bone marrow-derived mesenchymal stem cells (hBM-MSCs) according to the effect of transplantation on AD pathology, including PET/CT neuroimaging, immune status indicated by microglial numbers and autophagic capacity, neuronal survival, and cognition, in a 5 × FAD transgenic mouse model of AD. RESULTS: We demonstrated that hNTSCs showed a high proliferative capacity and great neurogenic properties in vitro. Compared with hBM-MSC transplantation, hNTSC transplantation markedly reduced Aß42 levels and plaque formation in the brains of the 5 × FAD transgenic AD mice on neuroimaging, concomitant with increased survival of hippocampal and cortex neurons. Moreover, hNTSCs strongly modulated immune status by reducing the number of microglia and the expression of the inflammatory cytokine IL-6 and upregulating autophagic capacity at 7 weeks after transplantation in AD models. Notably, compared with transplantation of hBM-MSCs, transplantation of hNTSCs significantly enhanced performance on the Morris water maze, with an increased level of TIMP2, which is necessary for spatial memory in young mice and neurons; this difference could be explained by the high engraftment of hNTSCs after transplantation. CONCLUSION: The reliable evidence provided by these findings reveals a promising therapeutic effect of hNTSCs and indicates a step forward the clinical application of hNTSCs in patients with AD.

Pre-transplant Dementia is Associated with Poor Survival After Hematopoietic Stem Cell Transplantation: A Nationwide Cohort Study with Propensity Score Matched Control.

OBJECTIVE: No previous study examined impact of dementia in the outcome of allogeneic hematopoietic stem cell transplantation (HSCT). We aimed to investigate overall survival (OS) of patients with dementia after receiving HSCT. METHODS: Among 8,230 patients who underwent HSCT between 2002 and 2018, 5,533 patients younger than 50 years were first excluded. Remaining patients were divided into those who were and were not diagnosed with dementia before HSCT (dementia group: n = 31; no dementia: n = 2,666). Thereafter, among 2,666 participants without dementia, 93 patients were selected via propensity-matched score as non-dementia group. Patients were followed from the day they received HSCT to the occurrence of death or the last follow-up day (December 31, 2018), whichever came first. RESULTS: With median follow-up of 621 days for dementia group and 654 days for non-dementia group, 2 year-OS of dementia group was lower than that of non-dementia group (53.3% [95% confidence interval, 95% CI, 59.0-80.2%] vs. 68.8% [95% CI, 38.0-68.2%], p = 0.076). In multivariate analysis, dementia had significant impacts on OS (hazard risk = 2.539, 95% CI, 1.166-4.771, p = 0.017). CONCLUSION: Our results indicated that patients diagnosed with dementia before HSCT have 2.539 times higher risk of mortality after transplantation than those not having dementia. With number of elderly needing HSCT is increasing, further work to establish treatment guidelines for the management of HSCT in people with dementia is needed.

Pre-transplant depression decreased overall survival of patients receiving allogeneic hematopoietic stem cell transplantation: a nationwide cohort study.

Studies investigating association of depression with overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) yielded conflicting results. A nationwide cohort study, which included all adult patients [n = 7,170; depression group, 13.3% (N = 956); non-depression group, 86.7% (N = 6,214)] who received allo-HSCT from 2002 to 2018 in South Korea, analyzed risk of pre-transplant depression in OS of allo-HSCT. Subjects were followed from the day they received allo-HSCT, to occurrence of death, or last follow-up day (December 31, 2018). Median age at allo-HSCT for depression and non-depression groups were 50 and 45 (p < 0.0001), respectively. Two groups also differed in rate of females (depression group, 55.8%; non-depression group, 43.8%; p < 0.0001) and leukemia (depression group, 61.4%; non-depression group, 49.7%; p < 0.0001). After a median follow-up of 29.1 months, 5-year OS rate was 63.1%. Cox proportional-hazard regression evaluated an adjusted risk of post-transplant mortality related to depression: OS decreased sequentially from no depression (adjusted hazard ratio [aHR] = 1) to pre-transplant depression only (aHR = 1.167, CI: 1.007-1.352, p = 0.04), and to having both depression and anxiety disorder (aHR = 1.202, CI: 1.038-1.393, p = 0.014) groups. Pre-transplant anxiety (anxiety only) did not have significant influence in OS. Additional medical and psychiatric care might be necessary in patients who experienced depression, especially with anxiety, before allo-HSCT.

Differential Impact of Cigarette Smoking on Fracture Risks in Subjective Cognitive Decline and Dementia: A Nationwide Longitudinal Study.

OBJECTIVE: We aimed to explore the differential impact of cigarette smoking on fracture risks in SCD and dementia. METHODS: A nationwide population-based cohort study design was used. Out of all the people aged 66 (n=1,555,103) who went through the National Screening Program from 2009-2014, 968,240 participants with eligible data were included in the study. Time-to-event was calculated as the duration between the NSPTA and fracture incidence. Cox proportional-hazard regression analyses were conducted to evaluate the risk of fractures. RESULTS: Increased risk of all [adjusted hazard ratio (aHR)=1.184; 95% confidence interval (CI)=1.184, 1.093-1.283], hip (aHR=1.518; 95% CI=1.168-4.972), vertebral (aHR=1.235; 95% CI=1.101-1.386) fractures were increased in current smokers with more than 20 or more pack years (≥20 py) of SCD group, after adjusting for all relevant confounding factors. In dementia group, however, current smokers ≥20 py were at reduced risk of hip fractures (aHR=0.249; 95% CI=0.089-0.97). CONCLUSION: There was a disparate influence of cigarette smoking on the fracture risks in SCD and dementia group. Further studies are warranted to explicate this phenomenon, and personalized preventive measures according to one's cognitive status are imperative, since risk factors of fractures can exert disparate influence on patients at different stage of cognitive trajectory.

Stem cell therapies for Alzheimer's disease: is it time?

PURPOSE OF REVIEW: Stem cell therapy has the potential to modify the disease of Alzheimer's disease. This article aims to describe the mechanisms of action, preclinical animal studies, human clinical trials, and challenges for the future direction of stem cell therapy for Alzheimer's disease. RECENT FINDINGS: Stem cells of diverse origins (embryonic, placental or umbilical cord blood, and induced pluripotent stem cells) and cell types (neural and mesenchymal stem cells) are widely studied in both animals and humans. SUMMARY: In terms of mechanism of actions, recent research focused on the interplay between amyloid-beta Aß (and tau), neurons, and glia. Stem cells can induce direct regeneration of neurons and synapses. They can also prevent activation of pro-inflammatory microglia, promote activation of anti-inflammatory microglia, inhibit astrogliosis, and promote nonreactive astrocytes. These effects in return may increase amyloid-beta (Aß) degradation, decrease the risk of the Aß cascade, repair injured neurons, and enhance synaptogenesis. Two completed and nine ongoing clinical trials using diverse stem cells and administration methods (intravenous, subcutaneous, and intra-cranial) were found for the treatment of Alzheimer's disease. Although stem cell therapy shows great potential to become a prospective treatment for Alzheimer's disease in the future, these studies are still in their early stages and more studies showing safety and efficacy are needed.

Stem Cell Therapy: A Prospective Treatment for Alzheimer's Disease.

Alzheimer's disease (AD) without cure remains as a serious health issue in the modern society. The major neuropathological alterations in AD are characterized by chronic neuroinflammation and neuronal loss due to neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau, plaques of ß-amyloid (Aß) and various metabolic dysfunctions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. This unmet need, however, could be met with stem cell technology that can be engineered to replace neuronal loss in AD patients. Although stem cell therapy for AD is only in its development stages, it has vast potential uses ranging from replacement therapy to disease modelling and drug development. Current progress with stem cells in animal model studies offers promising results for the new prospective treatment for AD. This review will discuss the characteristics of AD, current progress in stem cell therapy and remaining challenges and promises in its development.

Fatigue as a core symptom in major depressive disorder: overview and the role of bupropion.

Fatigue is one of the most common symptoms found in both community and medical care settings. Fatigue may imply a prodromal or residual symptom of major depressive disorder or an adverse reaction to antidepressant treatment. Fatigue may also compromise antidepressant treatment by delaying response to antidepressants. Despite the importance of fatigue as a core depressive symptom, data specific to the effects of fatigue on pharmacological treatment are still lacking. Bupropion is an atypical antidepressant, chemically unrelated to classical agents such as tricyclic antidepressants, selective serotonin reuptake inhibitors and other contemporary antidepressants. With a pharmacological profile that involves neurotransmitter reuptake inhibition, bupropion shares a broad range of biological properties with psychostimulants. The primary action mode of bupropion involves dopaminergic and noradrenergic neurotransmissions rather than serotonergic mechanisms, although its exact pharmacodynamic properties remain uncertain. Hence, it is possible that bupropion may play a role in the treatment of fatigue-related symptoms of major depressive disorder. This paper presents a brief overview of the clinical implications and neurobiology of major depressive disorder-related fatigue, as well as the pharmacological profile of bupropion and currently available clinical data related to its treatment of fatigue-related symptoms of major depressive disorder.