Assessment Scale-cognitive Subscale Scores Research Articles

Correlations between SHBG, Sex Hormones, Inflammation, and Neurocognitive Decline in Alzheimer's Disease:A Retrospective Study.

Alzheimer's Disease (AD) is characterized by a progressive neurodegenerative process leading to cognitive decline and functional impairment. Endocrine factors, particularly sex hormones and their binding proteins, play a critical role in AD pathophysiology. Understanding the relationship between these factors and AD is essential for developing targeted interventions. To investigate the potential links between sex hormone binding globulin (SHBG) levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in patients with AD. A retrospective case-control investigation was conducted with 110 AD patients who were admitted to our hospital from January 2021 to December 2023, and the patients were classified into either a mild neurocognitive impairment group (n=59) or a moderate to severe neurocognitive impairment group (n=51) according to their cognitive function. Correlation and regression analyses were conducted to examine relationships between variable factors. The study revealed a significant neurocognitive decline in AD patients with lower Mini-- Mental State Examination (MMSE) and higher AD Assessment Scale-Cognitive Subscale (ADAS- Cog) scores in the moderate to severe neurocognitive impairment group compared to the mild neurocognitive impairment group. Additionally, the moderate to severe neurocognitive impairment group significantly increased for SHBG, estradiol, progesterone inflammatory markers [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β)). It decreased for follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. Moreover, significant positive correlations were found between SHBG levels and ADAS-Cog scores, and significant negative correlations were found between SHBG levels and MMSE scores. FSH showed significant negative correlations with the MMSE score, while certain inflammatory markers demonstrated significant correlations with neurocognitive abilities. The correlation between sex hormones and inflammatory factors is weak. FSH, LH, SHBG, CRP, IL-6, TNF-α, and IL-1β are risk factors for neurocognitive impairment, while E2 and P are protective factors. The study provides evidence of significant correlations between SHBG levels, sex hormone profiles, inflammatory markers, and neurocognitive decline in AD patients.

Efficacy and safety of Neurocognitive Adaptive Training for Depression combined with SSRIs for treating cognitive impairment among patients with late-life depression: a 12-week, randomized controlled study

BackgroundThis randomized, open-label study examined the therapeutic effects of Neurocognitive Adaptive Training for Depression (NCAT-D) combined with selective serotonin reuptake inhibitors (SSRIs) on cognitive impairment among patients with late-life depression (LLD).MethodStudy data were collected from May 5, 2021, to April 21, 2023. Outpatients who met the diagnostic criteria for major depressive disorder according to the fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (i.e., a total score on the 17-item Hamilton Depression Rating Scale (HAMD-17) ≥ 18 and a total score on the Montreal Cognitive Assessment scale (MOCA) < 26) were recruited at Beijing Anding Hospital. These participants were randomly assigned to receive up to 12 weeks of NCAT-D and SSRIs treatment (n = 57) or SSRIs with a control treatment (n = 61). Primary outcomes included changes in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores from baseline to week 12 between the two groups. Assessments were conducted at baseline, after 2 weeks, 4 weeks, 8 weeks, and at 12 weeks. Mixed model repeated measures (MMRM) analysis was performed on modified intention-to-treat (mITT) and completer populations.ResultsThe full analysis set (FAS) included 118 patients (NCAT-D and SSRIs group, n = 57; SSRIs and Control group, n = 61). During the 12-week study period, MMRM analysis revealed a significantly greater reduction in cognitive function (as indicated by ADAS-cog total scores) from baseline to post-treatment in the NCAT-D and SSRIs group compared to the SSRIs and Control groups [(F (1,115) = 13.65, least-squares mean difference [95% CI]: −2.77 [− 3.73, − 1.81], p < 0.001)]. The intervention group showed a significantly greater reduction in HAMD-17 scores compared to the control group [MMRM, estimated mean difference (SE) between groups: −3.59 [− 5.02, − 2.15], p < 0.001]. There was no significant difference in the incidence of adverse events between the two groups.ConclusionsNCAT-D combined with SSRIs was efficacious and well tolerated in LLD patients with cognitive impairment.Trial registrationRegistered on October 18, 2022, at ClinicalTrials.gov Identifier: (#NCT05588102).

Impact of amyloid and cardiometabolic risk factors on prognostic capacity of plasma neurofilament light chain for neurodegeneration

BackgroundPlasma neurofilament light chain (NfL) is a blood biomarker of neurodegeneration, including Alzheimer’s disease. However, its usefulness may be influenced by common conditions in older adults, including amyloid-β (Aβ) deposition and cardiometabolic risk factors like hypertension, diabetes mellitus (DM), impaired kidney function, and obesity. This longitudinal observational study using the Alzheimer’s Disease Neuroimaging Initiative cohort investigated how these conditions influence the prognostic capacity of plasma NfL.MethodsNon-demented participants (cognitively unimpaired or mild cognitive impairment) underwent repeated assessments including the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) scores, hippocampal volumes, and white matter hyperintensity (WMH) volumes at 6- or 12-month intervals. Linear mixed-effect models were employed to examine the interaction between plasma NfL and various variables of interest, such as Aβ (evaluated using Florbetapir positron emission tomography), hypertension, DM, impaired kidney function, or obesity.ResultsOver a mean follow-up period of 62.5 months, participants with a mean age of 72.1 years (n = 720, 48.8% female) at baseline were observed. Higher plasma NfL levels at baseline were associated with steeper increases in ADAS-Cog scores and WMH volumes, and steeper decreases in hippocampal volumes over time (all p-values < 0.001). Notably, Aβ at baseline significantly enhanced the association between plasma NfL and longitudinal changes in ADAS-Cog scores (p-value 0.005) and hippocampal volumes (p-value 0.004). Regarding ADAS-Cog score and WMH volume, the impact of Aβ was more prominent in cognitively unimpaired than in mild cognitive impairment. Hypertension significantly heightened the association between plasma NfL and longitudinal changes in ADAS-Cog scores, hippocampal volumes, and WMH volumes (all p-values < 0.001). DM influenced the association between plasma NfL and changes in ADAS-Cog scores (p-value < 0.001) without affecting hippocampal and WMH volumes. Impaired kidney function did not significantly alter the association between plasma NfL and longitudinal changes in any outcome variables. Obesity heightened the association between plasma NfL and changes in hippocampal volumes only (p-value 0.026).ConclusionThis study suggests that the prognostic capacity of plasma NfL may be amplified in individuals with Aβ or hypertension. This finding emphasizes the importance of considering these factors in the NfL-based prognostic model for neurodegeneration in non-demented older adults.

Efficacy and safety of chinese herbal medicines combined with chemical drugs for alzheimer's disease: A systematic review and meta-analysis

Objective: To evaluate the efficacy and safety of Chinese herbal medicines (CHMs) combined with chemical drugs for the treatment of Alzheimer's disease (AD). Materials and Methods: Databases were searched to retrieve randomized controlled trials (RCTs) of CHMs combined with tacrine, galantamine, rivastigmine, donepezil, or memantine, following strict inclusion and exclusion criteria. Only research papers published in English, Chinese, and Japanese were considered. The primary outcome was the mini-mental state examination (MMSE) score and the secondary outcomes were AD assessment scale cognitive subscale (ADAS-Cog) score and safety evaluation. Meta-analysis was carried out using RevMan 5.3 and subgroup analysis was conducted to identify the sources of heterogeneity. Results: A total of 15 RCTs with 1386 participants were included in this study. Only donepezil was used in the retrieved literature. Meta-analyses showed that the combination of CHMs with donepezil led to significant improvement in the MMSE score (Z = 9.45; P &lt; 0.00001; weighted mean difference [WMD] =2.68, 95% confidence interval [CI]: 2.12–3.24) and a significant decrease in the ADAS-Cog score (Z = 5.53; P &lt; 0.00001; WMD = −3.79; 95% CI: −5.13–−2.44). Safety evaluation demonstrated that these combination treatments relieved adverse events such as insomnia (risk ratio [RR] =0.20, 95% CI: 0.06–0.68; P = 0.01) and hive (RR = 0.10; 95% CI: 0.01–0.73; P = 0.02). Conclusions: The combination of CHMs with a chemical drug like donepezil led to significant improvements in patient cognition as well as a better safety profile when compared to the application of a chemical drug alone.

Comparative Efficacy of Anti-Amyloid and Non-Antiamyloid Drugs for Treatment of Alzheimer’s Disease: A Network Meta-Analysis

BACKGROUND: Alzheimer’s disease is a degenerative neurological disorder that contributes 60-80% of all dementia cases, typically occurring at the age of 65 years. Currently available therapeutics for treatment are only capable of limiting the progression of cognitive decline. The focus of many Alzheimer’s disease drug therapies involves the hypothesized cause of pathogenesis in the disease, beta protein in the brain. Based on the Preferred Reporting Items for Meta-Analysis (PRISMA) for Network Meta-Analyses (NMA) framework, the present study was conducted to compare the efficacy of such drugs that target beta-amyloid directly or indirectly, with that of other treatments studied in randomized controlled trials. METHODS: Utilizing a network meta-analysis, direct and indirect comparisons between interventions could be done, providing a ranking of intervention in terms of efficacy in treating cognitive symptoms of Alzheimer’s disease. RESULTS: A total of 33 studies were included in four analyses of intervention trials that reported cognitive outcomes measured by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or Mini-Mental State Examination (MMSE) score. Based on the findings, anti-amyloid agents did not show a marked advantage over other therapies in improving cognitive scores. Results showed that parasympathomimetic agents were consistently ranked higher in terms of Surface Under the Cumulative Ranking (SUCRA) score, with anti-tau agents providing a possible superiority over all other interventions at improving MMSE scores for treatments lasting longer than 24 weeks. High-dose anti-amyloid therapies were effective at improving MMSE score in short term treatments lasting not more than 24 weeks but fall behind other drugs in longer durations. CONCLUSION: For better understanding on the choice of anti-amyloid and non-antiamyloid therapies, future well-designed large studies including safety outcome and cost- benefit analyses on the different interventions are recommended. Additionally, anti-tau therapies show a clearer potential over anti-amyloid therapies and should thus be given more focus in future drug research.

Drug Repositioning of Pioglitazone in Management and Improving the Cognitive Function among the Patients With Mild to Moderate Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Disease-modifying agents like Pioglitazone have shown promising effects on neuroinflammation and homeostasis of amyloid plaques, but there is a lack of research papers providing conclusive evidence. This study is aimed to determine the safety and efficacy of Pioglitazone in improving cognitive function in patients with mild-moderate Alzheimer's disease (AD). Trials published in the last 12 years were identified from PubMed, Scopus, Cochrane Central, and other trial registries. Five hundred twenty-five records were obtained, from which five studies were included for quantitative analysis. Studies comparing Pioglitazone with a suitable placebo or other oral hypoglycemic agent were considered for review. Data was extracted using a pretested form, which was followed by a risk of bias assessment (ROB) with Cochrane's ROB assessment tool. This meta-analysis included studies where Pioglitazone (15-30 mg) was compared to other oral hypoglycemic agents, placebo, or diabetic diet for a minimum duration of 6 months. Pioglitazone did not show a statistically significant improvement in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores [mean difference (MD): -1.16; 95% confidence interval (CI): -4.14-1.81]. By conducting sensitivity analysis with the removal of one study, significant efficacy was obtained [MD: -2.75; 95% CI: -4.84--0.66]. The Wechsler Memory Scale-Revised logical memory I (WMS-R) scores had a significant improvement in the Pioglitazone group [MD: 2.02; 95% CI: 0.09-3.95]. Pioglitazone is a safe medication that has a promising effect in slowing the advancement of AD.

The Role of Sirtuin 1 (SIRT1) in Neurodegeneration.

Sirtuins (SIRT) are a class of histone deacetylases that regulate important metabolic pathways and play a role in several disease processes. Of the seven mammalian homologs currently identified, sirtuin 1 (SIRT1) is the best understood and most studied. It has been associated with several neurodegenerative diseases and cancers. As such, it has been further investigated as a therapeutic target in the treatment of disorders such as Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD). SIRT1 deacetylates histones such as H1 lysine 26, H3 lysine 9, H3 lysine 56, and H4 lysine 16 to regulate chromatin remodeling and gene transcription. The homolog has also been observed to express contradictory responses to tumor suppression and tumor promotion. Studies have shown that SIRT1 may have anti-inflammatory properties by inhibiting the effects of NF-κB, as well as stimulating upregulation of autophagy. The SIRT1 activators resveratrol and cilostazol have been shown to improve Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores in AD patients. In this review, we aim to explore the various roles of SIRT1 with regard to neuroprotection and neurodegeneration.

Unknown treatment effects of donepezil in Alzheimer’s disease: Network analysis of three double‐blind randomized, placebo‐controlled, clinical trials

AbstractBackgroundPsychometric network analysis is an alternative theoretically‐driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer’s disease differently than was previously assumed and consequently detect unknown treatment effects.MethodBased on individual participant data, extracted from three double‐blind, randomized placebo‐controlled clinical trials, psychometric networks were computed on observed Alzheimer’s Disease Assessment Scale Cognitive Subscale scores at baseline (N = 1,554) and on predicted change scores at 24 weeks of follow‐up for participants who received donepezil (N = 797) or placebo (N = 484).ResultA novel conceptualization of cognitive impairment in Alzheimer’s disease was displayed through the baseline network, that had 90% (n = 27) positive statistically significant (p&lt;0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change networks. The donepezil change network had more statistically significant (p&lt;0.05) positive associations and a higher global strength (n = 15; S = 1.22; p = 0.03), than the placebo network (n = 8; S = 0.57), suggesting that for those who were treated with donepezil cognition is a more unified construct. Less for those given placebo. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network, suggesting that comprehension of spoken language is most sensitive to pharmaceutical interventions.ConclusionOverall, psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer’s disease, points to previously unknown treatment effects and highlights well‐defined aspects that may translate into future treatment targets.

Plasma tau and neurofilament light chain as biomarkers of Alzheimer's disease and their relation to cognitive functions.

Alzheimer's disease (AD) dementia is the most frequent cause of neurodegenerative dementia. The cognitive and behavioral symptoms associated with this disorder often have overlapping characteristics, potentially resulting in delayed diagnosis or misdiagnosis. This study aimed to assess the level of peripheral blood neurofilament light chain (NfL) and total tau (t-tau) protein in AD patients and investigate their relationship with cognitive impairment. The study included 80 participants of both sexes between the ages of 60 to 85 years. The participants were divided into two groups, consisting of 40 individuals in the control group (mean age 75±6.6 years) who had no cognitive or functional impairments and 40 AD patients (mean age 74.98±5.03 years). This study utilized the DSM-5 diagnostic criteria for major or mild neurocognitive disorder attributed to Alzheimer's disease (AD). The clinical and biochemical features of all participants were documented, and the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-cog) scores were evaluated. Sandwich ELISA was employed to determine serum NfL and t-tau protein levels. The median serum NfL and t-tau protein levels in AD patients were significantly higher than those of the controls (47.84 pg/ml versus 17.66 pg/ml and 12.05 pg/ml versus 11.13 pg/ml, respectively). Age was positively correlated with NfL, t-tau levels, and ADAS-cog. Although elevated NfL and t-tau protein levels may play a role in disease progression, their diagnostic value for AD was limited.

Combined metabolic activators improve cognitive functions in Alzheimer’s disease patients: a randomised, double-blinded, placebo-controlled phase-II trial

BackgroundAlzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress.MethodsHere, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients.ResultsWe showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment.ConclusionOur results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis.Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131

Effects of Melissa officinalis Extract Containing Rosmarinic Acid on Cognition in Older Adults Without Dementia: A Randomized Controlled Trial.

Previous in vitro and in vivo studies on Alzheimer's disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-β fibrils as well as the oligomerization and deposition of amyloid-β protein. Melissa officinalis (M. officinalis) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia. This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia. This study included individuals who were diagnosed with subjective or mild cognitive impairment (n = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer's Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability. There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups. These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension.

Plasma adiponectin levels predict cognitive decline and cortical thinning in mild cognitive impairment with beta-amyloid pathology

BackgroundBlood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer’s disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aβ) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aβ on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aβ conditions (Aβ [+] and Aβ [−]) in individuals with mild cognitive impairment (MCI).MethodsOf 156 participants with MCI from the longitudinal cohort study of Alzheimer’s Disease Neuroimaging Initiative (ADNI), 31 were Aβ (−) and 125 were Aβ (+) as determined by CSF analysis. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aβ conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined.ResultsOf the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aβ (+) and (−) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aβ (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aβ (+) condition (beta = − 0.004, p = 0.012 for the right side; beta = − 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aβ (−) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aβ status.ConclusionPlasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aβ (+) MCI.

Selective Serotonin Reuptake Inhibitor-Treatment Does Not Show Beneficial Effects on Cognition or Amyloid Burden in Cognitively Impaired and Cognitively Normal Subjects.

Preclinical studies indicate that selective serotonin reuptake inhibitors (SSRI) have beneficial effects on Alzheimer-related pathologies. Therefore, the aim of this study was to evaluate the influence of SSRI-treatment on amyloid burden in 18F-Florbetapir-positron emission tomography (PET) and on cognition in cognitively normal and cognitively impaired subjects. We included n = 755 cognitively impaired and n = 394 cognitively normal participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) that underwent at least one 18F-Florbetapir-PET. Standardized uptake ratios (SUVR) and the Alzheimer Disease Assessment Scale-cognitive subscale (ADAS) scores as well as follow-up results were compared between subgroups with a history of SSRI-treatment (SSRI+) and without SSRI-treatment (SSRI-) as well as in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. 18F-Florbetapir-PET did not show significant differences of SUVR between the SSRI+ and SSRI- groups in both, cognitively impaired and cognitively normal participants. There were no differences in subgroups of SSRI+/Depression+ and SSRI+/Depression- and SSRI-/Depression+ and SSRI-/Depression-. However, SUVR showed a dose-dependent inverse correlation to the duration of medication in cognitively normal and in cognitively impaired patients. SRRI-treatment did not show an effect on ADAS scores. Furthermore, there was no effect on follow-up SUVR or on follow-up ADAS scores. Overall, SSRI-treatment did not show beneficial effects on amyloid load nor on cognition.

Season of birth and vulnerability to the pathology of Alzheimer's disease: an in vivo positron emission tomography study.

This study used positron emission tomography to examine whether the seasonal birth effect as an exogenic indicator of early life environmental factors influenced vulnerability to Alzheimer's disease (AD) pathology in the elderly. We analysed datasets from the Alzheimer's Disease Neuroimaging Initiative, which included the data for 234 cognitively normal (CN) individuals and patients with mild cognitive impairment (MCI) (n=114) and AD dementia (n=38). As an index of amyloid β (Aβ)/tau accumulation, the 18 F-AV-45- and 18 F-AV-1451-standardized uptake value ratios (SUVRs) were compared between groups of spring-to-summer births and fall-to-winter births by analysis of covariance. In addition, a multiple linear regression analysis was performed to determine whether the season of birth was a predictor of 18 F-AV-45 and/or 18 F-AV-1451 SUVRs, for which a difference was observed. Seasonal birth difference was a good predictor of 18 F-AV-1451 SUVR. We found that participants with a fall-to-winter birth showed lower 18 F-AV-1451 SUVRs than those with a spring-to-summer birth in both the CN and MCI/AD groups, after correcting for the effect of age, sex, years of education, and Alzheimer's Disease Assessment Scale cognitive subscale score, that could possibly affect tau accumulation. Participants with a fall-to-winter birth showed less tau accumulation than those with a spring-to-summer birth after accounting for the factors that could affect tau accumulation. Our findings showed a vulnerability to tau pathology in participants with a fall-to-winter birth, which may be caused by perinatal or postnatal brain damage due to the risk factors associated with the cold season.

Blood D-Amino Acid Oxidase Levels Increased With Cognitive Decline Among People With Mild Cognitive Impairment: A Two-Year Prospective Study.

BackgroundDysregulation of N-methyl-D-aspartate receptor (NMDAR) neurotransmission has been reported to be implicated in the pathogenesis of Alzheimer’s disease (AD). D-amino acid oxidase (DAO), responsible for degradation of NMDAR-related D-amino acids such as D-serine, regulates NMDAR function. A cross-section study found that serum DAO levels were positively related with the severity of cognitive aging among elderly individuals. This 2-year prospective study aimed to explore the role of DAO levels in predicting the outcome of patients with very early-phase AD, such as mild cognitive impairment (MCI).MethodsFifty-one patients with MCI and 21 healthy individuals were recruited. Serum DAO levels and cognitive function, measured by the AD assessment scale-cognitive subscale and the Mini-Mental Status Examination, were monitored every 6 months. We employed multiple regressions to examine the role of DAO concentration in cognitive decline in the 2-year period.ResultsFrom baseline to endpoint (24 months), serum DAO levels increased significantly, and cognitive ability declined according to both cognitive tests in the MCI patients. Among the healthy individuals, DAO concentrations also increased and Mini-Mental Status Examination scores declined; however, AD assessment scale-cognitive subscale scores did not significantly change. Further, DAO levels at both months 12 and 18 were predictive of cognitive impairment at month 24 among the MCI patients.ConclusionsTo our knowledge, this is the first study to demonstrate that blood DAO levels increased with cognitive deterioration among the MCI patients in a prospective manner. If replicated by future studies, blood DAO concentration may be regarded as a biomarker for monitoring cognitive change in the patients with MCI.

Traditional East Asian Herbal Medicine Treatment for Alzheimer's Disease: A Systematic Review and Meta-Analysis.

Alzheimer’s disease (AD) is a leading progressive neurodegenerative disease worldwide, and its treatment is a challenging clinical problem. This review was conducted to evaluate the efficacy and safety of herbal medicine for AD treatment. The PubMed, CENTRAL, EMBASE, CNKI, OASIS, KTKP, and CiNii databases were searched until June 2020 for randomized controlled trials (RCTs) on herbal medicine for AD, and a meta-analysis of 57 RCTs was conducted. For cognitive function, herbal medicine significantly improved the Mini-Mental State Examination (MMSE) and AD Assessment Scale-Cognitive Subscale (ADAS-cog) scores compared with conventional medicine. The MMSE scores showed no significant difference between the groups treated with herbal medicine and donepezil; however, herbal medicine significantly lowered the ADAS-cog score. Acori Graminei Rhizoma-containing and Cnidii Rhizoma-containing herbal medicine significantly improved the MMSE and ADAS-cog scores compared with conventional medicine. Ginseng Radix-containing herbal medicine showed a positive, but not statistically significant, tendency toward improving the MMSE score compared with conventional medicine. Herbal medicine with conventional medicine significantly improved the MMSE, ADAS-cog, and Montreal Cognitive Assessment (MoCA) scores compared with conventional medicine, and herbal medicine with donepezil also significantly improved these scores compared with donepezil. Acori Graminei Rhizoma or Cnidii Rhizoma-containing herbal medicine with conventional medicine significantly improved the MMSE and ADAS-cog scores compared with conventional medicine. Ginseng Radix-containing herbal medicine + conventional medicine significantly improved the MMSE score, but not the ADAS-cog score, compared with conventional medicine. For behavioral and psychological symptoms of dementia, the Neuropsychiatry Inventory (NPI) score was not significantly different between herbal and conventional medicines. Herbal medicine with conventional medicine significantly improved the NPI and Behavioral Pathology in Alzheimer’s Disease Rating Scale scores compared with conventional medicine. The NPI score showed no significant difference between the groups treated with herbal medicine and placebo. Furthermore, herbal medicine with conventional medicine significantly lowered plasma amyloid beta levels compared with conventional medicine alone. Herbal medicine, whether used alone or as an adjuvant, may have beneficial effects on AD treatment. However, owing to the methodological limitations and high heterogeneity of the included studies, concrete conclusions cannot be made.

Cognitive impairment networks in Alzheimer's disease: Analysis of three double-blind randomized, placebo-controlled, clinical trials of donepezil

Psychometric network analysis is an alternative theoretically-driven analytic approach that has the potential to conceptualize cognitive impairment in Alzheimer's disease differently than was previously assumed and consequently detect unknown treatment effects. Based on individual participant data, extracted from three double-blind, randomized placebo-controlled clinical trials, psychometric networks were computed on observed Alzheimer's Disease Assessment Scale Cognitive Subscale scores at baseline (N=1,554) and on predicted change scores at 24 weeks of follow-up for participants who received donepezil (N=797) or placebo (N=484). A novel conceptualization of cognitive impairment in Alzheimer's disease was displayed through the baseline network, that had 90% (n=27) positive statistically significant (p<0.05) associations, and a most central aspect of ideational praxis. Following 24 weeks, treatment effects emerged via the differences between the change score networks. The donepezil network had more statistically significant (p<0.05) positive associations and a higher global strength (n=15; S=1.22; p=0.03), than the placebo network (n=8; S=0.57). This suggests that for those who were treated with donepezil compared with placebo, cognition is a more unified construct. The main aspects of change in cognitive impairment were comprehension of spoken language for the donepezil network and spoken language ability for the placebo network. Comprehension of spoken language apears to be most sensitive to psychopharmaceutical interventions and should therefore be closely monitored. Overall, our psychometric network analysis presents a new conceptualization of cognitive impairment in Alzheimer's disease, points to previously unknown treatment effects and highlights well-defined aspects of cognitive impairment that may translate into future treatment targets.

The Effectiveness and Safety of Chemical Drugs Combined with Acupuncture for Alzheimer's Disease: A Systematic Review and Meta-Analysis

Introduction: Acupuncture has been applied with chemical drugs to treat Alzheimer's disease (AD) in the clinic. Whether such combination is effective and safe should be studied although it is recommended by some researchers.&lt;br/&gt; Methods: To explore the effectiveness and safety of acupuncture combined with chemical drugs for AD, databases like PubMed, Web of Science were searched to retrieve randomized controlled trials (RCTs) on AD treated with acupuncture and chemical drugs to perform meta-analysis. The risk of bias in each study was assessed using the Cochrane risk of bias tool. Meta- analysis was performed using RevMan 5.3.&lt;br/&gt; Results: Five studies were included in which only donepezil combined with acupuncture was evaluated. Acupuncture combined with donepezil showed a significant difference in effectiveness rate [RR=1.45, 95% CI (1.19, 1.77), P =0.0002] compared with donepezil. On the comparison of mini-mental state examination (MMSE) score and Alzheimer's disease assessment scale cognitive subscale (ADAS-Cog) score there was no difference. However, after one trial with severe AD patients was removed, acupuncture combined with donepezil showed better effect than donepezil alone.&lt;br/&gt; Conclusion: Acupuncture combined with donepezil could work on AD at the early stage or being mild, implying that acupuncture could be a complementary therapy for AD at the early stage or being mild. Besides, scalp acupuncture seems to be more effective on improving cognitive function. However, this conclusion must be considered cautiously, given the small sample size and lack of trials with high quality. Therefore, more high-quality, multicenter, prospective RCTs with large sample sizes are needed to further clarify the effect of acupuncture combined with chemical drugs for AD.

Repeated Transcranial Magnetic Stimulation for Improving Cognition in Patients With Alzheimer Disease: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial.

BackgroundAlzheimer disease has no known cure. As existing pharmacologic interventions only modestly slow cognitive decline, there is a need for new treatments. Recent trials of repetitive transcranial magnetic stimulation (rTMS) have reported encouraging results for improving or stabilizing cognition in patients diagnosed with Alzheimer dementia. However, owing to small samples and lack of a well-controlled double-blind design, the results to date are inconclusive. This paper presents the protocol for a large placebo-controlled double-blind study designed with sufficient statistical rigor to measure the efficacy of rTMS treatment in patients with Alzheimer dementia.ObjectiveThe objectives are to (1) recruit and enroll up to 200 eligible participants, (2) estimate the difference in treatment effects between active treatment and sham treatment, (3) estimate the difference in treatment effects between two doses of rTMS applications, (4) estimate the duration of treatment effects among responders to active rTMS treatment, and (5) estimate the effect of dementia severity on treatment outcomes among patients receiving active rTMS treatment.MethodsWe have designed our study to be a double-blind, randomized, placebo-controlled clinical trial investigating the short- and long-term (up to 6 months) benefits of active rTMS treatment at two doses (10 sessions over 2 weeks and 20 sessions over 4 weeks) compared with sham rTMS treatment. The study will include patients aged ≥55 years who are diagnosed with Alzheimer disease at an early to moderate stage and have no history of seizures and no major depression. The primary outcome measure is the change in the Alzheimer Disease Assessment Scale-Cognitive Subscale score from pretreatment to posttreatment. Secondary outcomes are changes in performance on tests of frontal lobe functioning (Stroop test and verbal fluency), changes in neuropsychiatric symptoms (Neuropsychiatric Inventory Questionnaire), and changes in activities of daily living (Alzheimer Disease Co-operative Study-Activities of Daily Living Inventory). Tolerability of the intervention will be assessed using a modification of the Treatment Satisfaction Questionnaire for Medication. We assess participants at baseline and 3, 5, 8, 16, and 24 weeks after the intervention.ResultsAs of November 1, 2020, we have screened 523 individuals, out of which 133 were eligible and have been enrolled. Out of the 133 individuals, 104 have completed the study. Moreover, as of November 1, 2020, there has been no serious adverse event. We anticipate that rTMS will considerably improve cognitive function, with effects lasting up to 3 months. Moreover, we expect rTMS to be a well-tolerated treatment with no serious side effect.ConclusionsThis protocol design will allow to address both the rTMS active treatment dose and its short- and long-term effects compared with sham treatment in large samples.Trial RegistrationClinicalTrials.gov NCT02908815; https://clinicaltrials.gov/ct2/show/NCT02908815International Registered Report Identifier (IRRID)DERR1-10.2196/25144

Combined Metabolic Activators Improves Cognitive Functions in Alzheimer's Disease

Alzheimer’s disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. Here, we analysed the brain transcriptomics data of more than 600 AD patients using genome-scale metabolic models and provided supporting evidence of mitochondrial dysfunction related to the pathophysiologic mechanisms of AD progression. Subsequently, we investigated, in a rat model of AD, the oral administration of Combined Metabolic Activators (CMA), consisting of NAD+ and glutathione precursors, to explore the effect for improvement of biological functions in AD. CMA includes L-serine, nicotinamide riboside, N-acetyl-L-cysteine, and L-carnitine tartrate, salt form of L-carnitine. The study revealed that supplementation of the CMA improved the AD-associated histological parameters in the animals. Finally, we designed a randomized, double-blinded, placebo-controlled human phase 2 clinical trial and showed that the administration of CMA improves cognitive functions in AD patients. As decreased AD Assessment Scale-cognitive subscale (ADAS-Cog) score is the indicator of the improved cognitive function in AD patients, we observed a significant decrease of ADAS-Cog scores on Day 84 vs Day 0 (Log2FC= -0.37, (29% improvement), p-value=0.00001) in the CMA group. We also observed a significant decrease in the placebo group on Day 84 vs Day 0 (Log2FC= -0.19, (14% improvement), p-value=0.001) possibly due to the recommendations of exercise and Mediterranean diet to all AD patients and/or a placebo effect apparent in the early stages of AD clinical trials. A comprehensive analysis of the human plasma metabolome and proteome revealed that plasma levels of proteins and metabolites associated with redox metabolism are significantly improved after treatment. In conclusion, our results show that treating AD patients with CMA leads to enhanced cognitive functions, suggesting a role for such a therapeutic regime in treating AD and other neurodegenerative diseases. Funding: This work was financially supported by ScandiBio Therapeutics and Knut and Alice Wallenberg Foundation. The authors would like to thank the Metabolon Inc. (Durham, USA) for generation of metabolomics data, and ChromaDex Inc. (Irvine, CA, USA) for providing NR. AM and HY acknowledge support from the PoLiMeR Innovative Training Network (Marie Sklodowska-Curie Grant Agreement No. 812616) which has received funding from the European Union’s Horizon 2020 research and innovation programme. Declaration of Interest: AM, JB and MU are the founder and shareholders of ScandiBio Therapeutics. The other authors declare no competing interests. Ethical Approval: All experiments for the treatment of the animals were approved by the Ethics Committee of Ataturk University, and were conducted following the National Institutes of Health Guide for Care and Use of Laboratory Animals.