Transmission of Alzheimer's disease-associated microbiota dysbiosis and its impact on cognitive function: evidence from mice and patients.

Spouses of Alzheimer's disease (AD) patients are at a higher risk of developing incidental dementia. However, the causes and underlying mechanism of this clinical observation remain largely unknown. One possible explanation is linked to microbiota dysbiosis, a condition that has been associated with AD. However, it remains unclear whether gut microbiota dysbiosis can be transmitted from AD individuals to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. We, therefore, set out to perform both animal studies and clinical investigation by co-housing wild-type mice and AD transgenic mice, analyzing microbiota via 16S rRNA gene sequencing, measuring short-chain fatty acid amounts, and employing behavioral test, mass spectrometry, site-mutations and other methods. The present study revealed that co-housing between wild-type mice and AD transgenic mice or administrating feces of AD transgenic mice to wild-type mice resulted in AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment in the wild-type mice. Gavage with Lactobacillus and Bifidobacterium restored these changes in the wild-type mice. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of microbiota. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3ß at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. Pending confirmative studies, these results provide insight into a potential link between the transmission of AD-associated microbiota dysbiosis and development of cognitive impairment, which underscore the need for further research in this area.

Transmission of Alzheimer's Disease-Associated Microbiota Dysbiosis and its Impact on Cognitive Function: Evidence from Mouse Models and Human Patients.

Spouses of Alzheimer's disease (AD) patients are at higher risk of developing AD dementia, but the reasons and underlying mechanism are unknown. One potential factor is gut microbiota dysbiosis, which has been associated with AD. However, it remains unclear whether the gut microbiota dysbiosis can be transmitted to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. The present study found that co-housing wild-type mice with AD transgenic mice or giving them AD transgenic mice feces caused AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment. Gavage with Lactobacillus and Bifidobacterium restored these changes. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of oral and gut microbiota and its impact on cognitive function. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3ß at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. These results provide insight into a potential link between gut microbiota dysbiosis and AD and underscore the need for further research in this area.

Case report: Treatment of psychiatric symptoms for an acromegalic patient with pituitary adenoma.

Acromegalic patients always demonstrate a wide range of clinic manifestations, including typical physical changes such as acral and facial features, as well as untypical neuropsychiatric and psychological disturbances. However, there is still a lack of clinical guidance on the treatment for acromegalic patients with psychiatric comorbidities. We therefore share this case to provide a reference for clinicians to manage the acromegalic patients with psychiatric symptoms. This case report describes a 41-year-old male with an 8-year history of acromegaly due to growth hormone-secreting pituitary adenoma, the maximum cross-sectional area of which was 42 mm × 37 mm demonstrated by pituitary magnetic resonance imaging (MRI). The patient received conservative medicine treatment by regularly injecting with Sandostatin LAR 10 mg per month. Two days before admission, he suddenly presented with an acute psychotic episode. In addition to the typical acromegaly-associated changes, his main clinical presentations were olfactory/auditory hallucinations, reference/persecutory delusions, instable emotion and impulsive behavior. Considering the schizophrenic-like psychoses and course features, he was diagnosed with Brief Psychotic Disorder according to Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) after a multidisciplinary consultation and evaluation. He was prescribed Aripiprazole, which had less extrapyramidal symptoms and minimal influence on prolactin elevation, with the dose of 5 mg per day to control the psychiatric symptoms and he responded quite well. At the time of discharge and the follow-up 2 month later, the patient was stable without recurrence of any psychotic symptoms. The levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1) 1 week after discharge were 2.22 ng/mL [normal range (0-2.47 ng/mL)] and 381 µg/L [normal range (94-284 µg/L)], respectively, which were similar to those before the psychotic episode. Results from this report further supported that small dose of Aripiprazole had little influence on hormonal levels and the development of pituitary macroadenoma. This particular case emphasizes the importance for the clinician to master and carefully identify the possible symptoms of mental disorders associated with acromegaly, and also highlights the need for further investigation in more efficient treatment strategies for acromegalic cases with psychiatric comorbidities.

Preoperative homocysteine modifies the association between postoperative C-reactive protein and postoperative delirium.

Background: Homocysteine and C-reactive protein (CRP) may serve as biomarkers of postoperative delirium. We set out to compare the role of blood concentration of homocysteine versus CRP in predicting postoperative delirium in patients. Materials and methods: In this prospective observational cohort study, the plasma concentration of preoperative homocysteine and postoperative CRP was measured. Delirium incidence and severity within 3 days postoperatively were determined using the Confusion Assessment Method and Confusion Assessment Method-Severity algorithm. Results: Of 143 participants [69% female, median (interquartile range, 25th-75th) age of 71 (67-76) years] who had knee or hip surgery under general anesthesia, 44 (31%) participants developed postoperative delirium. Postoperative plasma concentration of CRP was associated with postoperative delirium incidence [adjusted odds ratio (OR) per one standard deviation change in CRP: 1.51; 95% Confidence Interval (CI): 1.05, 2.16; P = 0.026], and severity [in which each one standard deviation increase in postoperative CRP was associated with a 0.47 point (95% CI: 0.18-0.76) increase in the severity of delirium, P = 0.002] after adjusting age, sex, preoperative Mini-Mental State Examination score and the days when postoperative CRP was measured. A statistically significant interaction (adjusted P = 0.044) was also observed, in which the association between postoperative plasma concentration of CRP and postoperative delirium incidence was stronger in the participants with lower preoperative plasma concentrations of homocysteine compared to those with higher preoperative levels. Conclusion: Pending validation studies, these data suggest that preoperative plasma concentration of homocysteine modifies the established association between postoperative plasma concentration of CRP and postoperative delirium incidence.

Peripheral body temperature rhythm is associated with suicide risk in major depressive disorder: a case-control study.

BACKGROUND: Patients with major depressive disorder (MDD) may have an abnormal peripheral body temperature rhythm, but its relationship with suicidal risk and the response to treatment with antidepressants remain unknown. AIMS: This study aimed to investigate the feature of peripheral body temperature in patients with MDD and its relationship with suicide risk before and after treatment with antidepressants. METHODS: This is a prospective case-control study. Patients diagnosed as MDD were enrolled into MDD group. Healthy subjects who matched in terms of gender, age and body mass index were enrolled into normal control (NC) group. The 24-hour peripheral body temperatures were monitored by TM' Holter the next day after assessment. Patients with MDD were re-assessed after a 2-week treatment with antidepressants. All temperature data were fitted into cosine curves by Python. RESULT: There were 41 patients with MDD, and 21 NC participants enrolled and completed the baseline assessments before the treatment. Patients with MDD were further divided into subgroup of with suicide risk or without suicide risk. In patients with MDD, the mesor of peripheral body temperature rhythm was higher in both patients with (36.17 (0.30)) and without suicide risk (36.22 (0.27)) than the mesor in NC participants before treatment (35.84 (0.38), Z=11.82, p=0.003, Kruskal-Wallis test). The phase-delay of temperature before treatment was greater in patients with MDD with suicidal risk (4.71 (1.68)) in comparison with those without suicidal risk (3.05 (2.19)) and NC participants (3.19 (1.82), Z=9.68, p=0.008, Kruskal-Wallis test). Moreover, phase-delay of temperature was associated with suicide risk in patients with MDD before treatment (OR=1.046, 95% CI: 1.009 to 1.085, p=0.015, unadjusted; OR=1.080, 95% CI: 1.020 to 1.144, p=0.009, adjusted by age and sex). CONCLUSION: Patients with MDD might have abnormal peripheral body temperature. The abnormal phase-delay of peripheral body temperature may indicate suicide risk in patients with MDD, depending on validation in large-scale cohorts.

The Effects of Propofol and Sevoflurane on Postoperative Delirium in Older Patients: A Randomized Clinical Trial Study.

BACKGROUND: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown. OBJECTIVE: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane. METHODS: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2, and 3. RESULTS: A total of 209 participants (71.2±6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (p = 0.119, Chi-square test), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5±0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3±0.5, p = 0.049, Student's t-test). CONCLUSION: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis.

Retinal nerve fiber layer thickness is associated with hippocampus and lingual gyrus volumes in nondemented older adults.

OBJECTIVES: Abnormal retina structures, such as thinner retinal nerve fiber layer (RNFL), have been frequently reported in patients with Alzheimer's disease (AD). However, the association between RNFL and brain structures in cognitively normal adults remains unknown. We therefore set out to conduct a cross-sectional investigation to determine whether RNFL thickness is associated with brain structure volumes in nondemented older adults. METHODS: We measured RNFL thickness by optical coherence tomography and brain structure volumes by 3 T magnetic resonance imaging. Cognitive function was assessed using the Chinese version of Repeatable Battery for the Assessment of Neurological Status. Pearson correlation was initially employed to screen for the potential associations among RNFL thickness, brain structure volumes and cognitive function. And then, multivariable linear regression models were conducted to further examine such associations adjusting for possible confounding factors, including age, sex, years of education and the estimated total intracranial volume (eTIV). RESULTS: 113 participants (≥ 65 years old) were screened and 80 of them (mean age: 68 ± 5.3 years; 48% male) were included in the final analysis. RNFL thickness in temporal quadrant was associated with medial temporal lobes volumes [unadjusted: r = 0.155, P = 0.175; adjusted: ß = 0.205 (0.014, 0.383), P = 0.035], and especially associated with the hippocampus volume [unadjusted: r = 0.213, P = 0.062; adjusted: ß = 0.251 (0.060, 0.435), P = 0.011] after adjusted for age, sex, years of education and eTIV. Moreover, it showed that RNFL thickness in inferior quadrant [unadjusted: r = 0.221, P = 0.052; adjusted: ß = 0.226 (0.010. 0.446), P = 0.041] was significantly associated with occipital lobes volumes after the adjustment of age, sex, years of education and eTIV, and selectively associated with the substructure of lingual gyrus volume [unadjusted: r = 0.223, P = 0.050; adjusted: ß = 0.278 (0.058, 0.487), P = 0.014]. In addition, average RNFL thickness was associated with the cognitive domain of visuospatial/constructional [unadjusted: r = 0.114, P = 0.322; adjusted: ß = 0.216 (0.006, 0.426), P = 0.044] after the adjustment in these nondemented older adults. CONCLUSIONS: Quadrant-specific associations exist between RNFL thickness and brain regions vulnerable to aging or neurodegeneration in older adults with normal cognition. These findings would promote further investigations into using RNFL as a noninvasive and less expensive biomarker of neurocognitive aging and AD-related neurodegeneration.

Postoperative Delirium Is Associated with Long-term Decline in Activities of Daily Living.

BACKGROUND: Postoperative delirium is one of the most common complications in the elderly surgical population. However, its long-term outcomes remain largely to be determined. Therefore a prospective cohort study was conducted to determine the association between postoperative delirium and long-term decline in activities of daily living and postoperative mortality. The hypothesis in the present study was that postoperative delirium was associated with a greater decline in activities of daily living and higher mortality within 24 to 36 months after anesthesia and surgery. METHODS: The participants (at least 65 yr old) having the surgeries of (1) proximal femoral nail, (2) hip replacement, or (3) open reduction and internal fixation under general anesthesia were enrolled. The Confusion Assessment Method algorithm was administered to diagnose delirium before and on the first, second, and fourth days after the surgery. Activities of daily living were evaluated by using the Chinese version of the activities of daily living scale (range, 14 to 56 points), and preoperative cognitive function was assessed by using the Chinese Mini-Mental State Examination (range, 0 to 30 points). The follow-up assessments, including activities of daily living and mortality, were conducted between 24 and 36 months after anesthesia and surgery. RESULTS: Of 130 participants (80 ± 6 yr, 24% male), 34 (26%) developed postoperative delirium during the hospitalization. There were 32% of the participants who were lost to follow-up, resulting in 88 participants who were finally included in the data analysis. The participants with postoperative delirium had a greater decline in activities of daily living (16 ± 15 vs. 9 ± 15, P = 0.037) and higher 36-month mortality (8 of 28, 29% vs. 7 of 75, 9%; P = 0.009) as compared with the participants without postoperative delirium. CONCLUSIONS: Postoperative delirium was associated with long-term detrimental outcomes, including greater decline in activities of daily living and a higher rate of postoperative mortality.

The Reliability and Validity of the Chinese Version of Confusion Assessment Method Based Scoring System for Delirium Severity (CAM-S).

Previous studies showed that the Confusion Assessment Method based delirium severity evaluation tool (CAM-S) had good reliability and validity. However, there is no Chinese version of the CAM-S. Therefore, we set out to perform a prospective investigation in older Chinese patients who had total joint replacement surgery under general anesthesia in Tenth People's Hospital in Shanghai, P.R. China. A total of 576 participants, aged 60 years or older, were screened, 179 participants were enrolled, and 125 of them were included for the final analysis. Pre-operative evaluations were conducted one day before the surgery. Postoperative evaluations were conducted twice daily from postoperative day 1 to day 3. The incidence of postoperative delirium was 24.8%. The Chinese version of CAM-S [including a Short Form (CAM-S Short Form) and a Long Form (CAM-S Long Form)] had an optimal reliability reflected by internal consistency (Cronbach's α= 0.748 and 0.839 for CAM-S Short Form and CAM-S Long Form respectively), split-halves reliability (Pearson correlation coefficient = 0.372 and 0.384 for CAM-S Short Form and CAM-S Long Form respectively), and inter-rater reliability (intra-class correlation coefficients = 0.629 and 0.945 for CAM-S Short Form and CAM-S Long Form respectively). Additionally, the Chinese version of CAM-S also showed a good discriminate validity. The domain scores of CAM-S were inversely correlated with corresponding domain scores of the MMSE. Finally, a receiver operating characteristic (ROC) analysis obtained an optimal cutoff point of 2.5 for CAM-S Short Form and 3.5 for CAM-S Long Form in recognizing delirium diagnosed by CAM. The areas under the ROC were 0.989 (95% CI 0.972 - 1.000, p < 0.001) and 0.964 (95% CI 0.946 - 0.982, p < 0.001), respectively. These data suggest that the Chinese version of CAM-S has good reliability and validity in evaluating postoperative delirium in geriatric Chinese patients and may be a useful tool to assess the severity of delirium.

Retinal Nerve Fiber Layer Thinning Is Associated With Brain Atrophy: A Longitudinal Study in Nondemented Older Adults.

Backgrounds: Abnormal retinal nerve fiber layer (RNFL) thickness has been observed in patients with Alzheimer's disease (AD) and therefore suggested to be a potential biomarker of AD. However, whether the changes in RNFL thickness are associated with the atrophy of brain structure volumes remains unknown. We, therefore, set out a prospective investigation to determine the association between longitudinal changes of RNFL thickness and brain atrophy in nondemented older participants over a period of 12 months. Materials and Methods: We measured the RNFL thickness using optical coherence tomography (OCT) and brain structure volumes by 3T magnetic resonance imaging (MRI) before and after 12 months. Cognitive function was assessed using the Chinese version of Mini-Mental State Examination (CMMSE) and Repeatable Battery for the Assessment of Neurological Status. Associations among the changes of RNFL, brain structures and cognitive function were analyzed with Spearman correlation and multiple linear regression models adjusting for the confounding factors. Results: Fifty old participants were screened and 40 participants (mean age 71.8 ± 3.9 years, 60% were male) were enrolled at baseline. Among them, 28 participants completed the follow-up assessments. The average reduction of RNFL thickness was inversely associated with the decrease of central cingulate cortex volume after the adjustment of age and total intracranial volume (ß = -0.41, P = 0.039). Specifically, the reduction of RNFL thickness in the inferior, not other quadrants, was independently associated with the decline of central cingulate cortex volume after the adjustment (ß = -0.52, P = 0.006). Moreover, RNFL thinning, central cingulate cortex atrophy and the aggregation of white matter hyperintensities (WMH) were found associated with episodic memory in these older adults with normal cognition. Conclusions: RNFL thinning was associated with cingulate cortex atrophy and episodic memory decline in old participants. The longitudinal changes of RNFL thickness are suggested to be a useful complementary index of neurocognitive aging or neurodegeneration.

Multidimensional Approaches for A Case of Severe Adult Obsessive - Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a chronic, distressing and substantially impairing neuropsychiatric disorder, characterized by obsessions or compulsions. The current case describes a 44-year-old adult female diagnosed with OCD. The patient had an incomplete response to several SSRIs alone during her past treatment, and led a poor-quality life for at least three years. Current multidimensional approaches, including combined cognitive behavioral therapy (CBT) and the Selective Serotonin Reuptake Inhibitor (SSRI, Sertraline) with a small dose of antipsychotics (Aripiprazole) for augmentation, as well as familial support and resources from the internet were provided for the patient for six months. Standardized assessments with Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) every two months indicated significant reductions in obsessive and compulsive symptoms, with significant improvements in her social functioning and quality of life. A case such as this one provides preliminary support to multidimensional approaches for OCD treatment in order to achieve an optimal response, though further rigorous clinical trials are needed to provide more evidence.

Is the Best Evidence Good Enough: Quality Assessment and Factor Analysis of Meta-Analyses on Depression.

BACKGROUND: The quality of meta-analyses (MAs) on depression remains uninvestigated. OBJECTIVE: To assess the overall reporting and methodological qualities of MAs on depression and to explore potential factors influencing both qualities. METHODS: MAs investigating epidemiology and interventions for depression published in the most recent year (2014-2015) were selected from PubMed, EMBASE, PsycINFO and Cochrane Library. The characteristics of the included studies were collected and the total and per-item quality scores of the included studies were calculated based on the two checklists. Univariate and multivariate linear regression analyses were used to explore the potential factors influencing the quality of the articles. RESULTS: A total of 217 MAs from 74 peer-reviewed journals were included. The mean score of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was 23.0 of 27 and mean score of Assessment of Multiple Systematic Reviews (AMSTAR) was 8.3 of 11. Items assessing registration and protocol (14.2%, 37/217) in PRISMA and item requiring a full list of included and excluded studies (16.1%, 40/217) in AMSTAR had poorer adherences than other items. The MAs that included only RCTs, pre-registered, had five more authors or authors from Cochrane groups and the MAs found negative results had better reporting and methodological qualities. CONCLUSIONS: The reporting and methodological qualities of MAs on depression remained to be improved. Design of included studies, characteristics of authors and pre-registration in PROSPERO database are important factors influencing quality of MAs in the field of depression.