Moderate Alzheimer's Dementia Research Articles

Inter-hospital moderate and advanced Alzheimer's disease detection through convolutional neural networks

Electroencephalography (EEG) has been a fundamental technique in the identification of health conditions since its discovery. This analysis specifically centers on machine learning (ML) and deep learning (DL) methodologies designed for the analysis of electroencephalogram (EEG) data to categorize individuals with Alzheimer's Disease (AD) into two groups: Moderate or Advanced Alzheimer's dementia.Our study is based on a comprehensive database comprising 668 volunteers from 5 different hospitals, collected over a decade. This diverse dataset enables better training and validation of our results. Among the methods evaluated, the CNN (deep learning) approach outperformed others, achieving a remarkable classification accuracy of 97.45% for patients with Moderate Alzheimer's Dementia (ADM) and 97.03% for patients with Advanced Alzheimer's Dementia (ADA). Importantly, all the compared methods were rigorously assessed under identical conditions. The proposed DL model, specifically CNN, effectively extracts time domain features from EEG data in time, resulting in a significant reduction in learnable parameters and data redundancy.

Improved connectivity and cognition due to cognitive stimulation in Alzheimer's disease.

Due to the increasing prevalence of Alzheimer's disease (AD) and the limited efficacy of pharmacological treatment, the interest in non-pharmacological interventions, e.g., cognitive stimulation therapy (CST), to improve cognitive dysfunction and the quality of life of AD patients are on a steady rise. Here, we examined the efficacy of a CST program specifically conceptualized for AD dementia patients and the neural mechanisms underlying cognitive or behavioral benefits of CST. Using neuropsychological tests and MRI-based measurements of functional connectivity, we examined the (neuro-) psychological status and network changes at two time points: pre vs. post-stimulation (8 to 12 weeks) in the intervention group (n = 15) who received the CST versus a no-intervention control group (n = 15). After CST, we observed significant improvement in the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-cog), and the behavioral and psychological symptoms of dementia (BPSD) scores. These cognitive improvements were associated with an up-regulated functional connectivity between the left posterior hippocampus and the trunk of the left postcentral gyrus. Our data indicate that CST seems to induce short-term global cognition and behavior improvements in mild to moderate AD dementia and enhances resting-state functional connectivity in learning- and memory-associated brain regions. These convergent results prove that even in mild to moderate dementia AD, neuroplasticity can be harnessed to alleviate cognitive impairment with CST.

Intramuscularly Administered PLGA Microparticles for Sustained Release of Rivastigmine: In Vitro, In Vivo and Histological Evaluation

Rivastigmine is an acetylcholinesterase (AchE) and butyrylcholinesterase (BchE) inhibitor drug approved by the US Food and Drug Administration (FDA) for the treatment of mild to moderate dementia of Alzheimer's type. However, its first-pass metabolism and gastrointestinal side effects negatively affect the tolerability and efficacy of oral therapy. These adverse effects could be avoided with the use of a sustained -release formulation as an intramuscular (IM) administration system. The objective of this work was to develop polylactic co-glycolic acid (PLGA) microparticles for the sustained release of rivastigmine and to evaluate its stability during storage, tissue tolerance, in vitro release, and in vivo pharmacokinetics after its IM administration. The microparticles were made by the solvent evaporation emulsion method. A series of formulation parameters (the type of polymer used, the amount of polymer used, the initial amount of rivastigmine, and the volume of PVA 0.1% w/v) were studied to achieve an encapsulation efficiency (EE) and a rivastigmine load of 54.8 ± 0.9% and 3.3 ± 0.1%, respectively. The microparticles, whose size was 56.1 ± 2.8 μm, had a spherical shape and a smooth surface. FT-IR analysis showed that there is no chemical interaction between rivastigmine and the polymer. PLGA microparticles maintain rivastigmine retained and stable under normal (5 ± 3 °C) and accelerated storage (25 ± 2 °C and 60 ± 5 % RH) conditions for at least 6 months. The microparticles behaved as a sustained release system both in vitro and in vivo compared to non-encapsulated rivastigmine. The IM administration of the formulation in rats did not produce significant tissue damage. However, it is necessary to reproduce the experiments with multiple doses to rule out a negative effect in terms of tolerability in chronic treatment. To the best of our knowledge, this study is the only one that has obtained the sustained release of rivastigmine from PLGA microparticles after IM administration in an in vivo model.

Chitosan-Based Nanoparticles for Targeted Nasal Galantamine Delivery as a Promising Tool in Alzheimer's Disease Therapy.

Natural alkaloid galantamine is widely used for the treatment of mild to moderate Alzheimer's dementia. Galantamine hydrobromide (GH) is available as fast-release tablets, extended-release capsules, and oral solutions. However, its oral delivery can cause some unwanted side effects, such as gastrointestinal disturbances, nausea, and vomiting. Intranasal administration is one possible way to avoid such unwanted effects. In this work, chitosan-based nanoparticles (NPs) were studied as potential GH delivery vehicles for nasal application. The NPs were synthesized via ionic gelation and studied using dynamic light scattering (DLS) as well as by spectroscopic and thermal methods. The GH-loaded chitosan-alginate complex particles were also prepared as a way to modify the release of GH. The high loading efficiency of the GH was confirmed for both types of particles, at 67% for the GH-loaded chitosan NPs and 70% for the complex chitosan/alginate GH-loaded particles. The mean particle size of the GH-loaded chitosan NPs was about 240 nm, while the sodium alginate coated chitosan particles loaded with GH were expectedly bigger, with a mean particle size of ~286 nm. GH release profiles in PBS at 37 °C were obtained for both types of NPs, and it was found that the GH-loaded chitosan NPs allowed the prolonged release of the incorporated drug for a period of 8 h, while the complex GH-loaded chitosan/alginate NPs released the incorporated GH faster. The stability of the prepared GH-loaded NPs was also demonstrated after 1 year of storage at 5 °C ± 3 °C.

Magnetic resonance imaging measures of brain volumes across the EXPEDITION trials in mild and moderate Alzheimer's disease dementia.

IntroductionSolanezumab is a monoclonal antibody that preferentially binds soluble amyloid beta and promotes its clearance from the brain. The aim of this post hoc analysis was to assess the effect of low‐dose solanezumab (400 mg) on global brain volume measures in patients with mild or moderate Alzheimer's disease (AD) dementia quantified using volumetric magnetic resonance imaging (vMRI) data from the EXPEDITION clinical trial program.MethodsPatients with mild or moderate AD (EXPEDITION and EXPEDITION2) and mild AD (EXPEDITION3), were treated with either placebo or solanezumab (400 mg) every 4 weeks (Q4W) for 76 weeks. vMRI scans were acquired at baseline and at 80 weeks from 427 MRI facilities using a standardized imaging protocol. Whole brain volume (WBV) and ventricle volume (VV) changes were estimated at 80 weeks using either boundary shift integral (EXPEDITION and EXPEDITION2) or tensor‐based morphometry (EXPEDITION3).ResultsThe pooled cohort used for this study consisted of participants with vMRI at baseline and week 80 across the three trials. Analyzed patient subgroups comprised full patient cohort (N = 2933), apolipoprotein E (APOE) ε4+ carriers (N = 1835), and patients with mild (N = 2497) or moderate AD dementia (N = 428). No significant effect (all P‐values ≥.05) of treatment was observed in the pooled sample, individual trials, or subgroups of patients with mild or moderate AD or APOE ε4 carriers, in either WBV or VV change.DiscussionAnalysis of patients with mild or moderate AD dementia from baseline to 80 weeks using vMRI measures of WBV and VV changes suggested that low‐dose solanezumab was not linked to changes in volumes at 80 weeks. Analysis of the pooled cohort did not demonstrate an effect on brain volumes with treatment. Evaluation of a higher dose of solanezumab in the preclinical stage of AD is currently being undertaken.

Effect of masupirdine (SUVN-502) on cognition in patients with moderate Alzheimer's disease: A randomized, double-blind, phase 2, proof-of-concept study.

IntroductionThis study explored the efficacy and safety of a serotonin‐6 receptor antagonist, masupirdine, as adjunct treatment in patients with moderate Alzheimer's disease (AD) concomitantly treated with donepezil and memantine.MethodsThe effects of masupirdine were evaluated in patients with moderate AD dementia on background treatment with donepezil and memantine. Five hundred thirty‐seven patients were expected to be randomized in a 1:1:1 ratio, using permuted blocked randomization. After a 2‐ to 4‐week screening period, the study consisted of a 26‐week double‐blind treatment period, and a 4‐week washout period. The primary efficacy measure was the 11‐item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS‐Cog 11). Secondary efficacy measures were Clinical Dementia Rating Scale–Sum of Boxes, Mini‐Mental State Examination, 23‐item Alzheimer's Disease Co‐operative Study Activities of Daily Living, and 12‐item Neuropsychiatric Inventory. Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). A total of 564 patients were randomized to receive either daily masupirdine 50 mg (190 patients), masupirdine 100 mg (185 patients), or placebo (189 patients). The study is registered at ClinicalTrials.gov (NCT02580305).ResultsThe MMRM results showed statistically non‐significant treatment differences in change from baseline in ADAS‐Cog 11 scores at week 26, comparing each masupirdine dose arm to the placebo arm. No significant treatment effects were observed in the secondary evaluations.DiscussionMasupirdine was generally safe and well tolerated. Possible reasons for the observed trial results are discussed.Highlights Masupirdine was evaluated in moderate Alzheimer's disease patients.First trial in class with background treatment of donepezil and memantine.Masupirdine was generally safe and well tolerated.Possible reasons for the observed trial results are discussed.

Aducanumab and the “post-amyloid” era of Alzheimer research?

Aducanumab and the “post-amyloid” era of Alzheimer research?

Mobility and Depressive Symptoms in Persons With Mild Cognitive Impairment and Alzheimer Dementia.

Persons with mild cognitive impairment (MCI) and Alzheimer dementia (AD) often experience gait and balance disturbances and depressive symptoms alongside their cognitive impairment. The aim of this study was to explore the relationship between mobility and depressive symptoms in community-dwelling persons with MCI and mild to moderate AD. Ninety-nine participants with MCI and AD from the memory clinic at Oslo University Hospital, Ullevål, Norway, were included. The Balance Evaluation Systems Test (BESTest), 10-m walk test regular (gait speed), and dual task (naming animals, dual-task cost in percent) were used to assess mobility. The Cornell Scale for Depression in Dementia, with validated cut-off 5/6 points, was used to assess presence of depressive symptoms. Multiple regression analysis was used to explore the relationship between mobility (3 separate models) and depressive symptoms, controlled for demographic factors, comorbidity, and Mini-Mental State Examination. One-third of the participants had depressive symptoms, mean (SD) gait speed was 1.09 (0.3) m/s, and median (interquartile range) BESTest percent score was 81.5 (17.6). No statistically significant associations were found between depression and BESTest, gait speed or dual-task cost, neither in the simple models (P = 0.15-0.85), nor in the 3 multivariate models (P = 0.57-0.69). In this study, we found no associations between mobility and depressive symptoms in persons with MCI and AD recruited at a memory clinic. Few participants had major symptoms of depression, which may have influenced the results. Longitudinal studies are needed to explore the long-time associations between mobility and depression.Video Abstract available for more insights from the authors (see the Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A366).

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.

Estimating Progression Rates Across the Spectrum of Alzheimer's Disease for Amyloid-Positive Individuals Using National Alzheimer's Coordinating Center Data.

IntroductionPublished estimates of Alzheimer’s disease (AD) progression do not capture the full disease continuum. This study provides transition probabilities of individuals with amyloid-β (Aβ+) pathology across the disease continuum.MethodsPatient-level longitudinal data from the National Alzheimer’s Coordinating Center were used to estimate progression rates. Progression rates through five clinically defined AD stages—asymptomatic, mild cognitive impairment due to AD (MCI-AD), mild AD dementia, moderate AD dementia, severe AD dementia—and death were measured as transition probabilities. Rates were assessed in “incident” patients who recently entered the stage, controlling for covariates. Transition probabilities were generated from multinomial logit regression models that predicted an individual’s health state as a function of health state at the previous visit and adjusted for time between initial and follow-up visits, age, sex, years of education, and concomitant symptomatic AD medications.ResultsAnnual transition probabilities to more severe dementia stages for surviving incident Aβ+ patients were as follows: asymptomatic to MCI-AD, 40.8%; MCI-AD to mild AD dementia or worse, 21.8%; mild AD dementia to moderate AD dementia or worse, 35.9%; moderate AD dementia to severe AD dementia, 28.6%. Transition probabilities to less severe dementia stages were: 5.3% annual reversion from MCI-AD to asymptomatic, 3.0% mild AD dementia to MCI-AD, 1.8% moderate AD dementia to mild AD dementia, and 1.3% for severe AD dementia to moderate AD dementia.ConclusionsThese transition probabilities reflect the full continuum of AD progression in Aβ+ individuals and can be used to assess the impact of treatment on expected transitions.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00272-1.

Predicted Lifetime Health Outcomes for Aducanumab in Patients with Early Alzheimer's Disease.

IntroductionAlzheimer’s disease (AD) is a chronic and progressive neurodegenerative disease that places a substantial burden on patients and caregivers. Aducanumab is the first AD therapy approved by the US Food and Drug Administration to reduce a defining pathophysiological feature of the disease, brain amyloid plaques. In the phase 3 clinical trial EMERGE (NCT02484547), aducanumab reduced clinical decline in patients with mild cognitive impairment (MCI) due to AD and mild AD dementia and confirmed amyloid pathology.MethodsWe used a Markov modeling approach to predict the long-term clinical benefits of aducanumab for patients with early AD based on EMERGE efficacy data. In the model, patients could transition between AD severity levels (MCI due to AD; mild, moderate, and severe AD dementia) and care settings (community vs. institution) or transition to death. The intervention was aducanumab added to standard of care (SOC), and the comparator was SOC alone. Data sources for base-case and scenario analyses included EMERGE, published National Alzheimer’s Coordinating Center analyses, and other published literature.ResultsPer patient over a lifetime horizon, aducanumab treatment corresponded to 0.65 incremental patient quality-adjusted life-years (QALYs) and 0.09 fewer caregiver QALYs lost compared with patients treated with SOC. Aducanumab treatment translated to a lower lifetime probability of transitioning to AD dementia, a lower lifetime probability of transitioning to institutionalization (25.2% vs. 29.4%), delays in the median time to transition to AD dementia (7.50 vs. 4.92 years from MCI to moderate AD dementia or worse), and an incremental median time in the community of 1.32 years compared with SOC.ConclusionThe model predicted long-term benefits of aducanumab treatment in patients with MCI due to AD and mild AD dementia and their caregivers. The predicted outcomes provide a foundation for healthcare decision-makers and policymakers to understand the potential clinical and socioeconomic value of aducanumab.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00273-0.

Feasibility of reducing frailty components in older adults with Alzheimer's dementia: a randomized controlled home-based exercise trial (AD-HOMEX).

There is a need for interventions to reduce frailty in older people with Alzheimer's dementia (AD). The purpose of this study was to investigate the effect of a home-based multimodal exercise program for older adults with AD (AD-HOMEX) on frailty. A parallel single-blind randomized controlled trial comparing a home-based exercise program and usual care. A home-based program in Brazil. Forty individuals aged 65years or older with mild to moderate AD. The intervention group (IG) participated in a 16-week protocol involving three 60-minute sessions per week of progressive individualized physical exercises supervised by a physical therapist. The participants in the control group (CG) maintained their usual care. Frailty was assessed using the FRAIL questionnaire, the Edmonton Frail Scale (EFS) and a subjective assessment by the evaluator (SAE) at baseline and follow-up. Per-protocol analysis was performed. Thirty-five participants completed the program (IG=16; CG=19). Frailty improved in the IG based on the EFS (P=.004) and FRAIL (P≤.001). An interaction between group and time (P=.008) and a significant difference between times (P=.047) were found for the SAE responsiveness domain. An improvement in the classification of frailty (EFS and FRAIL) was found between times in the IG (P=.003) and between groups at follow-up (P=.027). A significant difference in the SAE classification was found between groups at follow-up (P=.034), with a worsening between times in the CG (P=.032). Interestingly, a more favorable frailty transition pattern was found in the IG based on both the EFS and FRAIL. AD-HOMEX seems to reduce frailty and improve frailty transition patterns. Our findings provide a further theoretical basis for designing home-based physical interventions as routine practice for older frail adults with AD.

Caring for Behavioral Symptoms of Dementia (CBD): A New Investigation into Cannabidiol for the Treatment of Anxiety and Agitation in Alzheimer's Dementia

<h3>Introduction</h3> Alzheimer's disease (AD) is a debilitating neurodegenerative disease accounting for 60-80% of dementia cases worldwide. In the United States alone, 13.8 million Americans are predicted to develop AD by 2050. The neuropsychiatric symptoms (NPS) of dementia affect up to 97% of AD patients over the course of their disease. A common NPS is agitation, characterized by problem behaviors that include combativeness and restlessness. Agitation is commonly associated with greater caregiver burden, shorter time to institutionalization, and anxiety. Anxiety symptoms affect 25-70% of the dementia population, and this wide range speaks to the inability to discern anxiety from agitation. Despite the pervasiveness of anxiety and agitation in the AD population, there are no FDA-approved medications that treat the behavioral symptoms of AD. Current treatments for these symptoms include time-intensive behavioral therapies and prescription of off-label antipsychotic medications that include an FDA warning of increased mortality in this population. Thus, the need for developing safe and efficacious treatments for anxiety and agitation in AD is dire. One potential treatment is cannabidiol (CBD), the major non-intoxicating constituent of cannabis sativa and industrial hemp, a variety of the cannabis plant that contains <0.3% delta9-tetrahydrocannabinol (THC), the main intoxicating constituent in cannabis, by weight. CBD modifies the endocannabinoid system and is thought to modulate effects via the 5-HT serotonergic system, μ-opioid receptors, and TRPV1/TRPV2 receptors. These interactions seem to result in an anxiolytic effect, as studies demonstrate CBD's ability to attenuate acute responses to stress in rats, act as a panicolytic in rats, and attenuate anxiety in humans. The utilization of CBD may extend beyond its role as an anxiolytic, as preclinical studies suggest widespread therapeutic impacts of CBD, including its ability to offer neuroprotective properties and inhibit tau hyperphosphorylation. Despite pre-clinical and animal evidence that CBD could modify neurodegeneration and behavioral symptoms in AD, no human clinical trials have investigated the impact of CBD on anxiety or agitation in AD. The present open-label clinical trial seeks to address this gap in knowledge by assessing the efficacy and tolerability of a high-CBD/low-THC sublingual solution as a treatment for anxiety and agitation in older adults with Alzheimer's disease. <h3>Methods</h3> An 8-week open-label clinical trial of an industrial hemp-derived custom-formulated high-CBD/low-THC sublingual solution developed by Dr. Staci Gruber, PhD, at McLean Hospital. We will recruit 12 research participants with mild to moderate Alzheimer's dementia and behavioral symptoms of anxiety with or without agitation. Our primary efficacy outcome measures are the anxiety domain of the Neuropsychiatric Inventory-Clinician Version (NPI-C) and the Generalized Anxiety Disorder-7 Item Scale (GAD-7). Our secondary safety outcome measures include continuous monitoring for serious adverse events and medication side effects, cognitive decline estimates from the Mini Mental Status Exam (MMSE), and the emergence of possible delirium from the 3D-Confusion Assessment Method (3D-CAM). Agitation and aggression domains on the NPI-C, scores on the Cohen-Mansfield Agitation Inventory (CMAI), and caregiver burden estimates from the Zarit Caregiver Burden Interview will be included as additional exploratory measures. <h3>Results</h3> Dr. Gruber's team is currently conducting a clinical trial for the treatment of anxiety in adults with moderate to severe anxiety using a similar custom-formulated high-CBD/low-THC sublingual solution. Preliminary analyses of Dr. Gruber's ongoing trial reveal that subjects experience significant reduction in anxiety symptoms along with improvements in mood, quality of life, and executive function over 4 weeks of treatment. Given these data and evidence of CBD's anxiolytic effects, we hypothesize that twice daily treatment with a high-CBD/low-THC solution in older adults with AD for 8 weeks will be associated with a statistically significant reduction in anxiety and agitation symptoms compared to baseline, as measured by our efficacy outcome measurements. We predict that the solution will be well-tolerated by the study population, as measured by our safety outcome measurements. <h3>Conclusions</h3> We seek a safe and effective treatment for the neuropsychiatric symptoms of anxiety and agitation in older adults with AD. With no current FDA-approved treatments for these behavioral symptoms, patients with AD risk ineffective therapies or mortality-associated antipsychotic treatments to address their NPS. Treating anxiety and agitation in these patients not only alleviates their symptoms but could also reduce caregiver burden and lengthen the time to institutionalization. CBD is a promising anxiolytic treatment that could advance our available treatment options for anxiety and agitation in AD. <h3>Funding</h3> The Spier Family Foundation

The Effect of Virtual Reality Applications on Balance and Gait Speed in Individuals With Alzheimer Dementia

Objective: The aim of the study is to investigate the effect of virtual reality applications on balance and gait speed in individuals with Alzheimer dementia. Method: The study consisted of 32 individuals diagnosed as mild or moderate Alzheimer dementia by the neurologist. The balance, fall risks, and gait speed were assessed. The training group was trained with games selected from different categories such as balance and aerobic exercises with Nintendo Wii virtual reality device for 6 weeks, 1 session of 30 minutes, 2 times a week. Results: The values of the 5-time sit-to-stand test and gait speed scores resulted that the training group had significantly lower scores than the control group. Tinetti balance score was decreased in the control group and increased in the training group. Conclusion: It is appropriate to add virtual reality applications to routine rehabilitation programs in order to increase patient's balance and gait speed in people with dementia. Clinical Trials.gov Identifier: NCT03928405

Impaired Cognitive Function is Associated with Motor Function and Activities of Daily Living in Mild to Moderate Alzheimer's Dementia.

The deterioration of cognitive and motor functions and activities of daily living is common in Alzheimer's dementia. The purpose of this study was to investigate the correlation and the strength of the relationship between cognitive function and motor function and activities of daily living after a diagnosis of Alzheimer's disease dementia. Sixty-three patients with mild to moderate Alzheimer's disease dementia in a community setting of South Korea were examined for cognitive and motor functions, and functional levels. The test or measures used for cognitive function were the Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), and Clinical Dementia Rating (CDR). The 10-meter walking test (10MWT), Berg Balance Scale (BBS), and Timed Up and Go Test (TUG) were used to examine motor function, while the Modified Barthel Index (MBI) and Katz Index (KI) were used to examining activities of daily living. The MMSE had a positive correlation with that from the BBS (r=.338, p<.05), MBI (r=.363, p<.05), and KI (r=.276, p<.05). The GDS was negatively correlated with BBS (r=.319, p<.05). Multivariate regression analysis showed that MMSE was a major explanatory variable for BBS (R2 =.115, β=.338, p<.05) MBI (R2 =.131, β=.363, p<.05), and KI (R2 =.076, β=.276, p<.05). The results of the present study show that cognitive function by MMSE is correlated with balance by BBS and activities of daily living by MBI and KI, and MMSE, which are tests or measures for cognitive function, can be explanatory variable to explain variations in the BBS, MBI, and KI in the persons with mild to moderate Alzheimer's dementia. It may mean that a decrease in cognitive function was found to affect motor function and activities of daily living. Based on this study, appropriate intervention approaches including physical exercise, should be considered for caring for persons with mild to moderate Alzheimer's dementia in a community setting.

Serum Concentrations of Cholinesterase Inhibitors in Patients With Alzheimer's Dementia Are Frequently Below the Recommended Levels.

BackgroundAcetylcholinesterase inhibitors (AChE-I) are recommended for the treatment of cognitive symptoms but also of behavioral and psychological symptoms in dementia. They are widely used not only in Alzheimer's disease, but also in other forms of dementia. Efficacy of treatment might depend on serum concentration of the respective AChE-I.ObjectiveIn patients with mild to moderate Alzheimer's dementia, we measured serum concentrations of hepatically metabolized donepezil and renally excreted rivastigmine and investigated possible modifiers. Additionally, we looked at correlations between serum concentrations and efficacy for both drugs.MethodsSerum concentrations of donepezil and rivastigmine were measured by liquid chromatography – tandem mass spectrometry (LC-MS/MS). Real-time quantitative polymerase chain reaction (PCR). Allele specific PCR were performed to determine CYP2D6 genotype and gene dose. Clinical efficacy was assessed by changes of the subtest wordlist delayed recall of the Consortium to Establish a Registry for Alzheimer's Disease-Neuropsychological Assessment Battery (CERAD-NAB).ResultsSixty-seven patients treated with a stable dosage of donepezil 10 mg (n=41) or rivastigmine 9.5 mg (n=26) were included. Mean serum concentration of donepezil and rivastigmine were 41.2 and 6.5 ng/ml, respectively. Serum concentrations were below the recommended range in 73% of the subjects in the donepezil group and in 65% of the participants in the rivastigmine group. When applying a dose-related reference, ranges 63% of patients in the donepezil group and 32% in the rivastigmine group had concentrations below the expected range. Gene dose, sex, and duration of treatment significantly predicted donepezil serum concentration (p=0.046, p=0.001, p=0.030 respectively). Only for rivastigmine did the serum concentration significantly contribute to the regression model predicting changes on the subtest word list delayed recall (β=0.472; p=0.019).ConclusionsSerum concentrations of about two thirds of the patients were below the recommended range. When not looking at absolute values but at the dose-related reference ranges, these numbers improved but still 32%, respectively 63% of patients had low serum concentrations. High serum concentrations of rivastigmine predicted clinical response to cognition. Therapeutic drug monitoring might help to identify the cause of poor clinical response to cognition and behavioral and psychological symptoms in patients with AChE-I treatment.

DEMENTIA: A COGNITIVE DISABILITY AND ROLE OF NON-PHARMACOLOGICAL INTERVENTION ALZHATV IN COGNITIVE REMEDIATION

DEMENTIA: A COGNITIVE DISABILITY AND ROLE OF NON-PHARMACOLOGICAL INTERVENTION ALZHATV IN COGNITIVE REMEDIATION

Antidementia Drug Therapy of Alzheimer's Dementia: Status 2018 and Outlook

Antidementia therapy: The clinical use of acetylcholinesterase inhibitors (AChE-I) for the symptomatic treatment of mild to moderate Alzheimer's dementia is recognized worldwide, despite its modest effectiveness. AChE-I may be continued to be used into severe stages of the dementia. In moderate to severe Alzheimer's dementia, the NMDA-receptor-antagonist Memantin is indicated.Lewy body dementia is treated as Alzheimer's disease; for Parkinson's dementia, there is a separate indication for rivastigmin. A worsening in motor symptoms may occur. There is no evidence-based antidementia drug therapy for frontotemporal or vascular dementia.Future Therapeutic Strategies: Disease modification is a major focus of current clinical trials. There are several clinical trials targeting anti-amyloid (phase 3) or anti-tau strategies. However, other therapeutic targets are persued, too. In current clinical trials, mild cognitive impairment due to Alzheimer's disease is targeted as the most meaningful study population.Implications for practice: At present, there just is symptomatic anti-dementive drug therapy available for Alzheimer's dementia, Parkinson's dementia and Lewy body dementia. Despite its modest effect sizes, treatment with these drugs is clinically relevant and seems to be cost-effective.

Comparison of cholinesterase inhibitor safety in real-world practice

IntroductionCholinesterase inhibitors (ChEIs) are widely used to treat mild to moderate Alzheimer's disease and related dementia. Clinical trials have focused on placebo comparisons, inadequately addressing within-class comparative safety. MethodsNew users of ChEIs in British Columbia were categorized into five study cohorts: low-dose donepezil, high-dose donepezil, galantamine, rivastigmine patch, and oral rivastigmine. Comparative safety of ChEIs assessed hazard ratios using propensity score adjusted Cox regression. ResultsCompared with low-dose donepezil, galantamine use was associated with a lower risk of mortality (adjusted hazard ratio: 0.84, 95% confidence interval: 0.60–1.18), cardiovascular serious adverse events (adjusted hazard ratio: 0.78, 95% confidence interval: 0.62–0.98), and entry into a residential care facility (adjusted hazard ratio: 0.72, 95% confidence interval: 0.59–0.89). DiscussionGiven the absence of randomized trial data showing clinically meaningful benefit of ChEI therapy in Alzheimer's disease, our study suggests preferential use of galantamine may at least be associated with fewer adverse events than treatment with donepezil or rivastigmine.

Association of hippocampal volume with gait variability in pre-dementia and dementia stages of Alzheimer disease: Results from a cross-sectional study.

Decreased hippocampal volume is a biomarker of Alzheimer disease (AD). The association of hippocampal volume with gait variability across the spectrum of AD, especially in early stages, has been few studied. The study aims to examine the association of hippocampal volume with the coefficient of variation (CoV) of stride time in individuals with mild and moderate to severe subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (na-MCI), amnestic mild cognitive impairment (a-MCI), and mild to moderate AD dementia. 271 individuals (79 mild SCI, 68 moderate to severe SCI, 47 na-MCI, 42 a-MCI and 35 mild to moderate AD dementia) were included in this cross-sectional study. Hippocampal volume was quantified from a three-dimensional T1-weighted MRI. CoV of stride time was recorded at self-selected pace with an electronic walkway. Age, sex, body mass index, number of drugs daily taken, history of falls, walking speed, type of MRI scanner, total intracranial volume, and white matter volume abnormality were used as covariates. Participants with moderate to severe SCI had a higher CoV of stride time compared to those with mild SCI and na-MCI (P < 0.010), and a higher hippocampal volume compared to other groups (P ≤ 0.001). Participants with moderate to severe SCI had increased hippocampal volume associated with increased CoV of stride time (coefficient of regression β = 0.750 with P = 0.041), while the other groups did not show any significant association. A positive association between greater hippocampal volume (i.e., better brain morphological structure) and an increased stride time variability (i.e., worse gait performance) in individuals with moderate to severe SCI is reported. This association confirms the key role of the hippocampus in gait control and suggests an inefficient compensatory mechanism in early stages of pathological aging like AD.