Moderate Alzheimer's Disease Patients Research Articles

Relationship between sarcopenic obesity and cognitive function in patients with mild to moderate Alzheimer's disease.

Previous research has linked sarcopenic obesity (SO) to cognitive function; however, the relationship between cognitive performance and SO Alzheimer's disease (AD) patients remains unclear. This study aimed to investigate their relationship in AD patients. One hundred and twenty mild to moderate AD patients and 56 normal controls were recruited. According to sarcopenia or obesity status, AD patients were classified into subgroups: normal, obesity, sarcopenia, and SO. Body composition, demographics, and sarcopenia parameters were assessed. Cognitive performance was evaluated using neuropsychological scales. Among the 176 participants, the prevalence of SO in the moderate AD group was higher than in the normal control group. The moderate AD group had the lowest appendicular skeletal muscle mass index (ASMI) and the highest percentage of body fat (PBF). Hypertension and diabetes were more prevalent in the SO group than in the normal group among the subgroups. The sarcopenia and SO groups exhibited worse global cognitive function compared to the normal and obesity groups. Partial correlation analysis revealed that ASMI, PBF, and visceral fat area were associated with multiple cognitive domains scores. In logistic regression analysis, after adjusting for confounders, obesity was not found to be associated with AD. However, sarcopenia (odds ratio (OR) = 5.35, 95% CI: 1.27-22.46) and SO (OR = 5.84, 95% CI: 1.26-27.11) were identified as independent risk factors for AD. SO was associated with cognitive dysfunction in AD patients. Moreover, the impact of SO on cognitive decline was greater than that of sarcopenia. Early identification and intervention for SO may have a positive effect on the occurrence and progression of AD.

White matter hyperintensities: a possible link between sarcopenia and cognitive impairment in patients with mild to moderate Alzheimer's disease.

Alzheimer's disease (AD) has been reported to be associated with sarcopenia. White matter hyperintensities (WMH) are common in AD patients. However, the effect of WMH on sarcopenia in AD remains unclear. We hence aimed to investigate the possible association between regional WMH volumes and sarcopenic parameters in AD. 57 mild to moderate AD patients and 22 normal controls (NC) were enrolled. Sarcopenic parameters were assessed, including appendicular skeletal mass index (ASMI), grip strength, 5-times sit-to-stand (5-STS) time, and gait speed. The volumes of periventricular hyperintensities (PVH) and deep white matter hyperintensities (DWMH) were quantified using 3D-slicer software. AD subjects exhibited a lower ASMI, a slower gait speed, an increased 5-STS time, and larger volumes of PVH and DWMH than those in the NC group. In AD subjects, total WMH and PVH volumes were related to cognitive impairment, particularly executive function decline. Moreover, total WMH volume and PVH volume were negatively correlated with gait speed across various clinical stages of AD. Multiple linear regression analysis showed that PVH volume was independently associated with 5-STS time and gait speed, whereas DWMH volume was only independently associated with gait speed. WMH volume was associated with cognitive decline and various sarcopenic parameters. It thereby suggested that WMH may serve as the connection between sarcopenia and cognitive dysfunction in AD. Further studies are needed to confirm these findings and to determine whether sarcopenia interventions reduce WMH volume and improve cognitive function in AD.

Correlation of muscle strength with cognitive function and medial temporal lobe atrophy in patients with mild to moderate Alzheimer's disease

Objective: To analyze the correlation of muscle strength with cognitive function and medial temporal lobe atrophy (MTA) in patients with mild to moderate Alzheimer's disease (AD). Methods: General information, sarcopenia-related indicators, neuropsychological tests and MTA score were collected in 80 confirmed AD patients (41 mild and 39 moderate patients) and 43 normal controls (NC) from the Memory Disorders Clinic of Department Of Neurology in the Second Affiliated Hospital of Soochow University between January and December 2021. Appendicular skeletal muscle mass index (ASMI), grip strength and 5-times sit-to-stand time and 6-m gait speed were used for assessing muscle mass, muscle strength and physical function, respectively. Cognitive function was assessed by Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment scale (MoCA), Memory and Executive Screening Scale (MES), Digit Symbol Substitution Test (DSST), Digital Span Test (DST) and Verbal Fluency Task (VFT), respectively. DST included Forward Digit Span Test (FDST) and Backward Digit Span Test (BDST). All the subjects underwent 3.0T coronal three-dimensional gradient echo sequence MRI. MTA scale was performed to evaluate the degree of medial temporal lobe atrophy. The differences in the sarcopenia-related indicators, cognitive score and MTA score were analyzed among the three groups, and the partial correlation analysis was performed between the inter-groups. Results: Eighty AD patients (24 males and 56 females) were included, aged (72±7) years old, with 41 mild and 39 moderate patients. Meanwhile, 43 NC included 19 males and 24 females, with a mean age of (70±6) years old. The disease duration in moderate AD patients was longer than that of mild AD patients [34.0 (25.0, 43.5) months vs 24.0 (11.0, 34.0) months, P<0.001]. The differences of sarcopenia-related indicators and MTA score among the three groups were statistically significant (all P<0.001), including 5-times sit-to-stand time [(13.6±1.8) s vs (11.5±1.7) s vs (10.3±1.9) s, P<0.001] and MTA score [2.0 (2.0, 3.0) vs 1.0 (1.0, 2.0) vs 0 (0, 0), P<0.001]. In neuropsychological tests, compared to the NC group, MMSE, MoCA, MES and VFT scores in mild and moderate AD groups were lower (all P<0.001); meanwhile, compared to the mild AD group, the moderate group had lower MMSE, MoCA, MES, DSST and VFT scores (all P<0.001). In sarcopenia-related indicators, muscle strength in particular was correlated with widespread cognitive functioning domains and MTA score in AD patients. Grip strength was positively correlated with MMSE, MoCA , MES, FDST (r=0.387, 0.418, 0.522 and 0.484, respectively, all P<0.001), DSST (r=0.327, P=0.006) and VFT score (r=0.354, P=0.003), and negatively correlated with MTA score (r=-0.631, P<0.001). 5-times sit-to-stand time was negatively correlated with MMSE, MoCA, MES, DSST, FDST, VFT score (r=-0.583, -0.587, -0.814, -0.591, -0.552 and -0.485, respectively, all P<0.001), and BDST (r=-0.355, P=0.003) strongly positively correlated with MTA score (r=0.836, P<0.001). ASMI was positively correlated with MMSE, MoCA, MES, DSST, FDST score (r=0.257, 0.238, 0.428, 0.282 and 0.364, respectively, all P<0.05), and negatively correlated with MTA score (r=-0.377, P=0.001). 6-m gait speed was positively correlated with MMSE, MoCA, MES, DSST, FDST score (r=0.419, 0.486, 0.699, 0.559 and 0.500, respectively, all P<0.001), BDST and VFT score (r=0.384、0.377, respectively, both P=0.001), and strongly negatively correlated with MTA score (r=-0.803, P<0.001). Conclusions: Patients with mild to moderate AD have widespread cognitive impairment. Muscle mass, muscle strength and physical function are all significantly impaired. Compared to muscle mass and physical function, decreased muscle strength is significantly associated with widespread cognitive decline and increased degree of medial temporal lobe atrophy.

Correlation between parameters related to sarcopenia and gray matter volume in patients with mild to moderate Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by brain atrophy and closely correlated with sarcopenia. Mounting studies indicate that parameters related to sarcopenia are associated with AD, but some results show inconsistent. Furthermore, the association between the parameters related to sarcopenia and gray matter volume (GMV) has rarely been explored. To investigate the correlation between parameters related to sarcopenia and cerebral GMV in AD. Demographics, neuropsychological tests, parameters related to sarcopenia, and magnetic resonance imaging (MRI) scans were collected from 42 patients with AD and 40 normal controls (NC). Parameters related to sarcopenia include appendicular skeletal muscle mass index (ASMI), grip strength, 5-times sit-to-stand (5-STS) time and 6-m gait speed. The GMV of each cerebral region of interest (ROI) and the intracranial volume were calculated by computing the numbers of the voxels in the specific region based on MRI data. Partial correlation and multivariate stepwise linear regression analysis explored the correlation between different inter-group GMV ratios in ROIs and parameters related to sarcopenia, adjusting for covariates. The 82 participants included 40 NC aged 70.13 ± 5.94years, 24 mild AD patients aged 73.54 ± 8.27years and 18 moderate AD patients aged 71.67 ± 9.39years. Multivariate stepwise linear regression showed that 5-STS time and gait speed were correlated with bilateral hippocampus volume ratios in total AD. Grip strength was associated with the GMV ratio of the left middle frontal gyrus in mild AD and the GMV ratios of the right superior temporal gyrus and right hippocampus in moderate AD. However, ASMI did not have a relationship to any cerebral GMV ratio. Among parameters related to sarcopenia, 5-STS time and gait speed were associated with bilateral hippocampus volume ratios at different clinical stages of patients with AD. Five-STS time provide an objective basis for early screening and can help diagnose patients with AD.

Acute response to cholinergic challenge predicts long‐term response to galantamine treatment in patients with Alzheimer's disease

AimsCholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's disease (AD) patients, but are associated with multiple side effects and only 20–40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of administration of a single dose of galantamine on central nervous system (CNS) functioning in mild to moderate AD patients and its potential to predict long‐term treatment response.MethodsThis study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double‐blind, placebo‐controlled cross‐over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open‐label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non‐responder based on their minimental state examination (MMSE), neuropsychiatric inventory (NPI) and disability assessment in dementia (DAD) scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non‐responders.ResultsA single dose of galantamine significantly reduced saccadic reaction time (−0.0099; 95% CI = −0.0195, −0.0003; P = .0430), absolute frontal EEG parameters in alpha (−14.9; 95% CI = −21.0, −8.3; P = .0002), beta (−12.6; 95% CI = −19.4, −5.3; P = .0019) and theta (−17.9; 95% CI = −25.0, −10.0; P = .0001) frequencies. Relative frontal (−1.669; 95% CI = −2.999, −0.339; P = .0156) and occipital (−1.856; 95% CI = −3.339, −0.372; P = .0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95% CI = 0.158, 2.475; P = .0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (−20.4; 95% CI = −31.6, −7.47; P = .0046), beta (−15.7; 95% CI = −28.3, −0.93; P = .0390) and theta (−25.9; 95% CI = −38.4, −10.9; P = .0024) EEG parameters and of relative frontal theta power (−3.27%; 95% CI = −5.96, −0.58; P = .0187) on EEG significantly distinguished responders (n = 11) from non‐responders (n = 32) after 6 months.ConclusionsThis study demonstrates that acute PD effects after single dose of galantamine are correlated with long‐term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.

Thermal analysis of Alzheimer’s disease prediction using random forest classification model

Missing and irregularly sampled data points are common in time-dependent data collected in Alzheimer's disease studies. As a result, time-series methods based on regular sampling cannot be applied directly to data without first undergoing pre-processing. In this paper developed to learn the relationship between pairs of data points at different times, we implement random forest model separations in time the input vector contains a summary of the time series history. Due to similar brain patterns and pixel intensities, the diagnosis of AD images to feature representation for categorization. Machine Learning approaches can learn things like representations from data. A 4-way classifier is used in this study to distinguish between Healthy Control (HC) and Mild Alzheimer's disease (AD), Very Mild AD, and Moderate AD patients. Experiments are carried out using the OASIS dataset, and the results are used to classify diseases into multiple categories. The Random Forest Classification Model was used to do a thermal analysis of Alzheimer's disease prediction. The random forest classifier models have been shown to consistently outperform their equivalents. The improved accuracy of tweaking the parameters of random forest classifiers demonstrated in this study work argues for its use in the classification of stages of Alzheimer's disease.

Effect of Age, Cognitive Impairment Severity, and Duration of Disease on Efficacy of Masupirdine in Moderate Alzheimer's Disease Patients: A Post Hoc Analysis of a Phase-2 Randomized Placebo Controlled Study Results

Alzheimer's disease (AD) is an age-related progressive neurodegenerative brain disorder with cognitive symptoms as a hallmark phenotype of the disease. Masupirdine, a pure serotonin 6 (5-HT6) receptor antagonist is being developed for the treatment of cognitive deficits in AD. The objective of the current study is the post hoc analysis of a multicenter, randomized, double-blind, parallel group, 26-week, placebo-controlled phase-2 study (NCT02580305) that evaluated the effects of masupirdine on cognition in patients with moderate AD. Methods: Masupirdine phase 2 study included AD patients of 50 to 85 years age, mini-mental state examination (MMSE) score of 12 to 20 and diagnosis of probable AD at least 1 year prior to the screening visit. The impact of age, cognitive impairment severity, and duration of disease since diagnosis on efficacy of masupirdine as assessed by 11-item version of the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog 11) was evaluated. Treatment effects were assessed by Cohen’s d effect size. Results: Cohen’s d effect size for change in ADAS-Cog 11 scores from baseline to week 26 ranged between ~0.2 and 0.4 for the subgroup of population with age ≤ 70 years, MMSE range of 18 to 20, and duration of disease over 4 years (since diagnosis). Conclusions: Considering the linear relationship between age and cognitive decline, masupirdine effects across the subgroups could be attributed to “slowing of cognitive decline”. The study provides important findings for design of future clinical trials. Further research is warranted to confirm the potential beneficial effects of masupirdine on cognition in AD patients.

Real-world Evaluation of Tolerability, Safety and Efficacy of Rivastigmine Oral Solution in Patients with Mild to Moderate Alzheimer's Disease Dementia.

ObjectiveThe purpose of this study is to investigate the safety, tolerability and efficacy of titrating dose of rivastigmine oral solution in patients with mild to moderate Alzheimer’s disease (AD) in Taiwan.MethodsWe recruited 108 mild to moderate AD patients with RivastⓇ (rivastigmine oral solution 2 mg/ml) treatment for 52 weeks. We recorded the demographic characteristics, initial cognition by mini-mental state examination (MMSE), initial global status by clinical dementia rating (CDR) with CDR-Sum of Boxes (CDR-SB), initial dose, and titrating dose at each visit. We investigated the adherence, proportion of possible side effects, optimal dose, and time to optimal dose. We demonstrated the proportion of cognitive decline and its possible risk factors.ResultsDuring the course, 9 patients discontinued the rivastigmine oral solution due to poor compliance or preference. Twelve out of 99 patients (12.1%) reported possible side effects. Among 87 patients, the mean age was 77.2 ± 9.0 years ago with female predominant (65.2%). The optimal dose was 3.6 ± 1.4 ml in average and 4 ml (n = 31, 35.6%) in mode. The duration to optimal dose was 12.5 ± 10.2 weeks and 24 weeks (n = 35, 40.2%) in mode. It presented 25% with cognitive decline in MMSE, 27% with global function decline in CDR and 63% with global function decline in CDR-SB.ConclusionWe demonstrated the clinical experience of rivastigmine oral solution in mild to moderate AD patients. It suggested rivastigmine oral solution 4ml is the optimal dose with 24 weeks to the optimal dose for at least one third of patients.

Preclinical and clinical biomarker studies of CT1812: A novel approach to Alzheimer's disease modification.

IntroductionAmyloid beta (Aβ) oligomers are one of the most toxic structural forms of the Aβ protein and are hypothesized to cause synaptotoxicity and memory failure as they build up in Alzheimer's disease (AD) patients’ brain tissue. We previously demonstrated that antagonists of the sigma‐2 receptor complex effectively block Aβ oligomer toxicity. CT1812 is an orally bioavailable, brain penetrant small molecule antagonist of the sigma‐2 receptor complex that appears safe and well tolerated in healthy elderly volunteers. We tested CT1812's effect on Aβ oligomer pathobiology in preclinical AD models and evaluated CT1812's impact on cerebrospinal fluid (CSF) protein biomarkers in mild to moderate AD patients in a clinical trial (ClinicalTrials.gov NCT02907567).MethodsExperiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer binding to synapses in vitro, to human AD patient post mortem brain tissue ex vivo, and in living APPSwe/PS1dE9 transgenic mice in vivo. Additional experiments were performed to measure the impact of CT1812 versus vehicle on Aβ oligomer‐induced deficits in membrane trafficking rate, synapse number, and protein expression in mature hippocampal/cortical neurons in vitro. The impact of CT1812 on cognitive function was measured in transgenic Thy1 huAPPSwe/Lnd+ and wild‐type littermates. A multicenter, double‐blind, placebo‐controlled parallel group trial was performed to evaluate the safety, tolerability, and impact on protein biomarker expression of CT1812 or placebo given once daily for 28 days to AD patients (Mini‐Mental State Examination 18–26). CSF protein expression was measured by liquid chromatography with tandem mass spectrometry or enzyme‐linked immunosorbent assay in samples drawn prior to dosing (Day 0) and at end of dosing (Day 28) and compared within each patient and between pooled treated versus placebo‐treated dosing groups.ResultsCT1812 significantly and dose‐dependently displaced Aβ oligomers bound to synaptic receptors in three independent preclinical models of AD, facilitated oligomer clearance into the CSF, increased synaptic number and protein expression in neurons, and improved cognitive performance in transgenic mice. CT1812 significantly increased CSF concentrations of Aβ oligomers in AD patient CSF, reduced concentrations of synaptic proteins and phosphorylated tau fragments, and reversed expression of many AD‐related proteins dysregulated in CSF.DiscussionThese preclinical studies demonstrate the novel disease‐modifying mechanism of action of CT1812 against AD and Aβ oligomers. The clinical results are consistent with preclinical data and provide evidence of target engagement and impact on fundamental disease‐related signaling pathways in AD patients, supporting further development of CT1812.

The Therapeutic Targets of Fingolimod (FTY720) Are Involved in Pathological Processes in the Frontal Cortex of Alzheimer's Disease Patients: A Network Pharmacology Study.

Background: The sphingosine-1-phosphate receptor (S1PR) modulator fingolimod (FTY720), which is commonly used as an immunomodulator in multiple sclerosis treatment, has recently been found to reduce pathological changes in the brain tissue of Alzheimer's disease (AD) animal models, but this has yet to be verified in human brain tissue. In this study, network pharmacology methods were applied to determine the potential pharmacological mechanisms of fingolimod in the frontal cortex of AD patients.Methods: The pharmacological macromolecular targets of fingolimod and fingolimod phosphate were downloaded from SwissTarget and DrugBank. Systematic intersection analysis of the expression profiles of brain frontal cortex tissues (423 AD tissues and 266 control tissues) was performed to obtain AD-associated fingolimod targets (F-ADGs). Immune cell infiltration analysis and a primary mouse cortical culture RNA-seq drug screen database were used to identify immune-related F-ADGs and cortex-related F-ADGs. Then, the expression values of F-ADGs were correlated with the disease severity score (MMSE score) of AD patients to identify severity-related F-ADGs. We also analyzed miRNA expression microarray data in the frontal cortex of AD patients associated with disease severity to obtain severity-related F-ADG-miRNAs.Results: A total of 188 F-ADGs were detected in the frontal cortices of AD patients and were enriched in biological processes such as synaptic signaling, inflammatory response, and response to oxygen-containing compounds. Eleven immune-related F-ADGs (like FPR1, BLNK.) and 17 cortex-related F-ADGs (like ALDH1L1, DUSP1.) were detected. Other F-ADGs, such as S1PR1 and GABBR2, although not classified into the above two categories, were still predicted by bioinformatics methods to play an important role in the development of AD. Two F-ADGs (GNAQ and MMP14) and 28 miRNAs (like miR- 323a-3p, miR-181a-5p.) were found to be associated with AD severity (MMSE 0-27 group). Fifteen F-ADGs (like ALDH1L1, FPR1, and IL6.) and 46 miRNAs (like miR-212-5p, miR-93-5p.) were found to be associated with mild or moderate dementia AD patients' severity (MMSE11-22 subgroup).Conclusions: Fingolimod may affect the brain frontal cortex function of AD patients in many different ways, such as affecting immune cell infiltration, nerve cell, or glial cell function, and synaptic function. miRNAs may also be involved. ALDH1L1, FPR1, S1PR1, and GABBR2 may be core drug targets.

Inter-band Bispectral Analysis of EEG Background Activity to Characterize Alzheimer's Disease Continuum.

The aim of this study was to characterize the EEG alterations in inter-band interactions along the Alzheimer's disease (AD) continuum. For this purpose, EEG background activity from 51 healthy control subjects, 51 mild cognitive impairment patients, 50 mild AD patients, 50 moderate AD patients, and 50 severe AD patients was analyzed by means of bispectrum. Three inter-band features were extracted from bispectrum matrices: bispectral relative power (BispRP), cubic bispectral entropy (BispEn), and bispectral median frequency (BispMF). BispRP results showed an increase of delta and theta interactions with other frequency bands and the opposite behavior for alpha, beta-1, and beta-2. Delta and theta interactions, along with the rest of the spectrum, also experimented a decrease of BispEn with disease progression, suggesting these bands interact with a reduced variety of components in advanced stages of dementia. Finally, BispMF showed a consistent reduction along the AD continuum in all bands, which is reflective of an interaction of the global spectrum with lower frequency bands as the disease develops. Our results indicate a progressive decrease in inter-band interactions with the severity of the disease, especially those involving high frequency components. Since inter-band coupling oscillations are related to complex and multi-scaled brain processes, these alterations likely reflect the neurodegeneration associated with the AD continuum.

AMBAR, an Encouraging Alzheimer's Trial That Raises Questions.

Grifols' recent Alzheimer Management by Albumin Replacement (“AMBAR”) study investigated the effects of plasmapheresis with albumin replacement, plus intravenous immunoglobulin (IVIG) in some subjects, in patients with mild-to-moderate Alzheimer's disease (AD). AMBAR was a phase IIb trial in the United States and a phase III trial in Europe. There were three treatment groups (plasmapheresis with albumin replacement; plasmapheresis with low dose albumin and IVIG; plasmapheresis with high dose albumin and IVIG) and sham-treated controls. Disease progression in pooled treated patients was 66% less than control subjects based on ADAS-Cog scores (p = 0.06) and 52% less based on ADCS-ADL scores (p = 0.03). Moderate AD patients had 61% less progression, based on both ADAS-Cog and ADCS-ADL scores, than their sham-treated counterparts (p-values 0.05 and 0.002), and their CDR-Sb scores declined 53% less than their sham-treated counterparts. However, ADAS-Cog and ADCS-ADL scores were not significantly different between actively-treated and sham-treated mild AD patients, although CDR-Sb scores improved vs. baseline for treated mild AD patients. Patients administered both IVIG and albumin had less reduction in brain glucose metabolism than sham-treated patients. Questions raised by these findings include: what mechanism(s) contributed to slowing of disease progression? Is this approach as effective in mild AD as in moderate AD? Must IVIG be included in the protocol? Does age, sex, or ApoE genotype influence treatment response? Does the protocol increase the risk for amyloid-related imaging abnormalities? How long does disease progression remain slowed post-treatment? A further study should allow this approach to be optimized.

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial.

We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aβ38, Aβ40, Aβ42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples (n = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients.Trial Registration: NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27

Estimating Life Expectancy and Lifetime Healthcare Costs for Alzheimer's Disease in Taiwan: Does the Age of Disease Onset Matter?

People with early onset Alzheimer's disease (EOAD) seem to suffer greater impact. But there is a lack of population-based studies on loss of life expectancy (LE) and lifetime healthcare costs. We conducted this study to estimate LE, expected years of life lost (EYLL), and lifetime healthcare costs for Alzheimer's disease (AD) in Taiwan stratified by onset age and gender, using a method which integrates the product of the survival function and the mean cost function over a lifetime horizon. We linked the National Health Insurance datasets with the National Mortality Registry and extrapolated the survival to lifetime to estimate the mean cumulative costs since the date of the first AD diagnosis using medical claims between 2001 and 2012. A total of 21,615 mild to moderate AD patients (including 20,358 late-onset (LOAD) and 1,257 EOAD) were recruited. The average onset age for EOAD was 61 years old, while that of LOAD was 78. Although the LE of EOAD was 4.8 years longer than that of LOAD due to younger age, the EYLL for the former was 8.7 years versus 1.7 years for the latter. EOAD also had higher lifetime healthcare costs than the LOAD group (USD$37,957±2,403 versus 33,809±786). Since EOAD patients had both higher EYLL and lifetime healthcare costs than LOAD, future studies should pay more attention to the needs of EOAD patients.

Medium-chain triglycerides improved cognition and lipid metabolomics in mild to moderate Alzheimer's disease patients with APOE4-/-: A double-blind, randomized, placebo-controlled crossover trial.

Previous clinical and animal studies suggested that medium-chain triglycerides (MCT) might be an alternative energy substrate for the brain and might benefit patients with Alzheimer's disease (AD), but the clinical evidence is not substantial or totally convincing. To investigate the effects of MCT on cognitive ability in patients with mild to moderate AD and explore the changes in peripheral blood metabolomics. A double-blind, randomized, placebo-controlled crossover study was undertaken in 53 mild to moderate AD patients. Participants were randomized between two sequences (placebo followed by MCT or MCT followed by placebo) and took MCT jelly or placebo jelly (canola oil) by mouth three times daily (total daily fat dose: 17.3g MCT, or 19.7g canola oil) for 30 days per phase. The primary outcome was cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Chinese version (ADAS-Cog-C). The secondary outcome was self-care as measured by the activities of daily living scale (ADL) and changes in plasma metabolites. This study showed a significant (p<0.01) reduction in ADAS-Cog-C scores between the MCT (2.62 points below baseline) and placebo interventions (2.57 points above baseline). Data from 46 (86.8%) APOE4-/- subjects who completed the entire study were analyzed. Changes in ADL scores were not significantly different between the MCT and placebo interventions (p>0.05). The concentrations of TC, HDL-C, β-hydroxybutyrate and acetoacetate were significantly higher in the MCT group than in the placebo group (p<0.05). Lysophosphatidylcholine 16:0 (LysoPC (16:0)), LysoPC (P-18:0), LysoPC (P-18:1(9Z)), LysoPC (20:2(11Z,14Z)), and LysoPC (22:5(4Z,7Z,10Z,13Z,16Z)) were significantly increased after MCT intervention, and the concentrations of LysoPC (18:0), palmitic acid, linoleic acid, oleic acid, and 7,12-dimethylbenz[a]anthracene were significantly decreased (p<0.05), whereas no significant changes appeared after the placebo intervention. Androstenedione concentration increased after placebo intervention. Furthermore, a significant negative correlation was observed between changes in LysoPC (P-18:1(9Z)) and ADAS-Cog-C scores after MCT intervention (r=-0.1472, p<0.05). MCT had positive effects on cognitive ability in mild to moderate AD patients with APOE4-/-. These effects of MCT might be related to the metabolism of LysoPC, oleic acid, linoleic acid and palmitic acid, in addition to the ketogenic effect. ChiCTR-IOR-16009737. WHO ICTRP Search Portal - http://apps.who.int/trialsearch/Default.aspx.

Distinguishing mild cognitive impairment from healthy aging and Alzheimer's Disease: The contribution of the INECO Frontal Screening (IFS).

Executive functions are affected differently in healthy aging, Mild Cognitive Impairment (MCI) and Alzheimer’s Disease (AD), and evaluating them is important for differential diagnosis. The INECO Frontal Screening (IFS) is a brief neuropsychological screening tool, developed to assess executive dysfunction in neurodegenerative disorders. Goals: We aimed to examine whether and how MCI patients can be differentiated from cognitively healthy controls (HC) and mild to moderate AD patients based on IFS performance. We also explored how IFS scores are associated with age, years of education, and depressive/anxious symptoms (as assessed by the Hospital Anxiety and Depression Scale). Method: IFS total scores were compared between 26 HC, 32 MCI and 21 mild to moderate AD patients. The three groups were matched for age and education. The Area Under the Curve (AUC) was analyzed and optimal cut-offs were determined. Results: Healthy participants had higher IFS scores than both clinical groups, and MCI patients had higher scores than AD patients. IFS showed high diagnostic accuracy for the detection of MCI (AUC = .89, p < .001) and AD (AUC = .99, p < .001), and for the differentiation between the clinical groups (AUC = .76, p < .001). We provide optimal cut-offs for the identification of MCI and AD and for their differentiation. We also found that, in general, higher education predicted higher IFS scores (no associations with age and depressive/anxious symptoms were observed). Altogether, these findings indicate that evaluating executive functions with the IFS can be valuable for the identification of MCI, a high-risk group for dementia, and for differentiating this condition from healthy aging and AD.

Transcranial Direct Current Stimulation Improves Cognitive Function in Mild to Moderate Alzheimer Disease: A Meta-Analysis.

The purpose of this meta-analysis was to evaluate the therapeutic effect of transcranial direct current stimulation (tDCS) on mild to moderate Alzheimer disease (AD) patients. PubMed, Embase, Web of Science, and Cochrane Library were searched until April 2018. The primary cognitive outcomes were extracted from included articles. A crude standardized mean difference with 95% CI was calculated by using fixed or random effect models. Seven studies with 146 patients were included in this meta-analysis. The pooled result showed that tDCS significantly improved cognitive function of AD patients (standardized mean difference=0.37; 95% CI, 0.09-0.65; P=0.01). Subgroup analyses showed that: a single session of tDCS was significantly effective (P<0.05) whereas repeated sessions of tDCS was not lower current density (0.06 mA/cm) (P>0.05) but not higher current density (0.08 mA/cm) significantly improved cognitive performance; stimulating the temporal cortex (P<0.05) but not the left dorsal lateral prefrontal cortex significantly improved cognitive function of AD patients; and improved cognitive function occurred in the group with higher education (P<0.05) but not in the group with lower education. Current evidence suggests that tDCS has a beneficial effect in mild to moderate AD patients. We must be cautious about the results of subgroup analysis given small sample sizes, and further well-designed studies with larger sample size are required to verify these results.

Neuropsychiatric symptoms differently affect mild cognitive impairment and Alzheimer's disease patients: a retrospective observational study.

Alzheimer's disease (AD) is the most common form of dementia characterized by the prevalent memory impairment. Mild cognitive impairment (MCI) may represent the early stage of AD, in particular when MCI patients show biomarkers consistent with AD pathology (MCI due to AD). Neuropsychiatric symptoms (NPS) frequently affect both MCI and AD patients. Cerebrospinal-fluid (CSF) tau and β-amyloid42 (Aβ42) levels are actually considered the most sensitive and specific biomarkers for AD neurodegeneration. In the present retrospective observational study, we evaluated CSF biomarkers and neuropsychological data (also including NPS measured by the neuropsychiatric inventory-NPI) in a population of patients affected by MCI due to AD compared with mild to moderate AD patients. We documented higher NPI scores in MCI compared with AD patients. In particular, sub-items related to sleep, appetite, irritability, depression, and anxiety were higher in MCI than AD. We also found the significant correlation between NPS and CSF AD biomarkers in the whole population of MCI and AD patients. Consistently, t-tau/Aβ42 ratio correlated with NPS in all the MCI and AD patients. These results suggest the more prevalent occurrence of NPS in MCI patients showing AD pathology and converting to dementia than AD patients. Moreover, a more significant degree of AD neurodegeneration, featured by high t-tau/Aβ42 ratio, correlated with more severe NPS, thus supposing that in MCI and AD patients a more extensive AD neurodegeneration is related to more severe behavioral disturbances.

Gender Differences in Neuropsychiatric Symptoms in Mild to Moderate Alzheimer's Disease Patients Undergoing Switch of Cholinesterase Inhibitors: A Post Hoc Analysis of the EVOLUTION Study.

Background: Alzheimer's disease (AD) is characterized by progressive cognitive decline, often associated with Behavioral and Psychological Symptoms of Dementia (BPSD). Acetylcholinesterase inhibitors (ChEi) may attenuate cognitive decline and mitigate BPSD. The EVOLUTION group found that the switch from oral ChEi to transdermal rivastigmine patch formulation resulted in improvement/stabilization in the frequency of clinically relevant BPSD, but gender-specific subgroup analyses were not reported.Methods: Participants underwent Neuropsychiatric Inventory to assess the frequency and severity of neuropsychiatric symptoms at baseline and 3 and 6 months after the switch from oral ChEi to transdermal rivastigmine patch. A descriptive post hoc analysis was conducted to assess whether there were gender-based differences in BPSD profile during the 6 months after the switch.Results: The entire sample consisted of 475 patients, 274 women and 201 men. Women were on average slightly older and with poorer cognitive performance (60.6% of the women had moderate-AD, defined as Mini-Mental State Examination [MMSE] score of 10–17, vs. 43.8% of men). In mild-AD patients (MMSE score 18–26), the frequency of BPSD did not change significantly over time and an association was found between gender and depression (odds ratio; OR [95% confidence interval; CI] female vs. male = 3.32 [1.44–7.67]), anxiety (2.42 [1.23–4.79]), apathy (2.25 [1.07–4.70]), nighttime behavior disturbances (3.97 [1.66–9.49]), and appetite/eating abnormalities (2.39 [1.10–5.18]). Moderate-AD female patients had euphoria more frequently than male patients (OR [95% CI] female vs. male = 3.67 [1.25–10.74]). The frequency of delusions, anxiety, and irritability decreased during the first 3 months after the switch, independently of gender.Conclusion: Mild-AD women tended to suffer more frequently from BPSD than men; in the 3 months after treatment switch, moderate-AD patients showed a decrease in delusions, anxiety, and irritability, with no significant differences between genders. Ad hoc studies to investigate this potential gender effect in AD could be well worthwhile.

Differential chemokine expression under the control of peripheral blood mononuclear cells issued from Alzheimer's patients in a human blood brain barrier model.

Growing evidence highlights the peripheral blood mononuclear cells (PBMCs) role and the chemokine involvement in the Alzheimer’s disease (AD) physiopathology. However, few data are available about the impact of AD PBMCs in the chemokine signature in a brain with AD phenotype. Therefore, this study analyzed the chemokine levels in a human blood brain barrier model. A human endothelial cell line from the immortalized cerebral microvascular endothelial cell line (hCMEC/D3) and a human glioblastoma U-87 MG cell line, both with no AD phenotype were used while PBMCs came from AD at mild or moderate stage and control patients. PBMCs from moderate AD patients decreased CCL2 and CCL5 levels in endothelial, and also CXCL10 in abluminal compartments and in PBMCs compared to PBMCs from mild AD patients. The CX3CL1 expression increased in endothelial and abluminal compartments with PBMCs from mild AD patients compared to controls. AD PBMCs can convert the chemokine signature towards that found in AD brain, targeting some chemokines as new biomarkers in AD.