Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer’s disease progression

Abstract We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer’s disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms. Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

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AFFECTIVE THEORY OF MIND IN PEOPLE WITH ALZHEIMER’S DISEASE

10.5327/1980-5764.rpda052 ◽

2021 ◽

Author(s):

Aline De Lucena ◽

Paulo Fernando Santos ◽

Marcia Cristina Dourado

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Emotional State ◽

Neuropsychiatric Symptoms ◽

Cross Sectional Study ◽

Social Situations ◽

Cross Sectional ◽

Emotional Reasoning ◽

Significant Difference ◽

Emotional Aspects

Background: In recent years, interest has been growing in cognitive and affective ToM functioning in individuals suffering from neurodegenerative disorders, such as Alzheimer’s disease (AD). However, the affective ToM has been less investigated. Objective: This study aims to compare affective ToM performance in persons with mild to moderate AD and healthy older controls (HOC), and its relationship with cognition. Methods: A cross-sectional study of 97 mild to moderate AD individuals and 40 HOC. To assess affective ToM, participants were administered a task that examines ability to comprehend the emotional situation nature along with the appropriate emotional state that one would experience in that situation. Assessments of cognition, dementia severity, functionality, awareness of disease and neuropsychiatric symptoms were completed for AD group. Results: Analyses of emotional reasoning indicated a group effect on performance. There was a significant difference between the AD and HOC groups in terms of their ability to understand situations of sadness, surprise, anger, and happiness, with the moderate AD showing the worst performance for all emotional situations. Ability to appropriately name the emotional state was significantly different for surprise, anger, and happiness, but not for sadness, with both AD groups showing lower performance for surprise and anger, and with the mild AD showing better performance for happiness. In both AD groups, ability to understand the emotional situation and to name the emotion was significantly correlated with cognitive impairment and awareness of disease. Neuropsychiatric symptoms were significantly correlated in moderate AD group. Conclusions: Impairment in understanding the emotional aspects of situations can lead moderate AD people to experience conflicts in family and social situations. Mild AD people can experience same conflicts when their preserved ability in understanding the emotional situation is underestimated.

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The Alzheimer’s Disease THErapy with NEuroaid II (ATHENE) Study: A Double-Blind Randomized Delayed-Start Trial to Assess the Safety and Efficacy of MLC901 (NeuroAiD™II) as an add-on Treatment to Cholinesterase Inhibitors or Memantine in Patients With Mild to Moderate Alzheimer's Disease

10.21203/rs.3.rs-494674/v1 ◽

2021 ◽

Author(s):

Christopher Chen ◽

Qingshu Liu ◽

Rejesh Babu Moorakonda ◽

Nagaendran Kandiah ◽

Boon Yeow Tan ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Events ◽

Cognitive Assessment ◽

Standard Treatment ◽

Serious Adverse Events ◽

Significant Difference ◽

Early Starters ◽

Modifying Effect ◽

Disease Modifying

Abstract BackgroundPreclinical and clinical studies indicate a role for MLC901 (NeuroAiDTMII) in Alzheimer’s Disease (AD). We investigated its safety and efficacy as add-on therapy to standard treatment and evaluated a disease modifying effect in mild to moderate AD.MethodsMild-moderate probable AD patients by NINCDS-ADRDA criteria, stable on acetylcholinesterase inhibitors or memantine (n=125) were randomized to receive MLC901 (early starters) or placebo (delayed starters) for 6 months, followed by a further 6 months during which all patients received MLC901, in a delayed-start design. The primary outcome measure was serious adverse events at 6 months, secondary outcomes included the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog) and other cognitive assessment scales.ResultsThere was no significant difference in the risk of serious adverse events between early and delayed starters at month (M) 6 (22.6% vs. 27.0%, risk difference = -4.4%, 90% CI -16.9 to 8.3%). Furthermore, there was no significant difference in the risk of adverse events, including the occurrence of stroke or vascular events, between early and delayed starters throughout the 12-month study period. The early-starters differed significantly on ADAS-Cog from the delayed-starters at M9 (mean difference -3.36, 95% CI -5.64 to -1.09) and M12 (mean difference -2.35, 95% CI -5.45 to 0.74). Other cognitive assessment scales showed trends in favor of MLC901.ConclusionsMLC901 is a safe adjunct to standard treatment for mild-moderate AD. There is no indication that the risk of any adverse events, including vascular, is increased with MLC901 in the study population. The cognitive outcomes provide support for a disease-modifying effect of MLC901 which requires confirmation in further studies. Clinical trial registration: ClinicalTrials.gov, NCT03038035. https://clinicaltrials.gov/ct2/show/NCT03038035

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SOCIAL COGNITION AND AWARENESS IN ALZHEIMER’S DISEASE

Innovation in Aging ◽

10.1093/geroni/igz038.441 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S120-S120

Author(s):

Marcia Dourado ◽

Tatiana Belfort ◽

José Simões Neto

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Social Cognition ◽

Social Functioning ◽

Neuropsychiatric Symptoms ◽

Consecutive Series ◽

Cross Sectional ◽

Significant Difference ◽

Impaired Awareness ◽

The Relationship

Abstract Social cognition is the capacity to interpret and predict another’s behavior according to beliefs, intentions, and emotions, and the ability to decode environmental stimuli in order to be better able to adapt to new situations. A key question is the relationship between social cognition and awareness in dementia. This study aimed to investigate the relation between social and emotional functioning (SEF) and awareness in Alzheimer's disease (AD). In a cross-sectional design, a consecutive series of 50 people with mild to moderate AD and their 50 family caregivers were assessed. The study variables were awareness, SEF, neuropsychiatric symptoms, cognition, working memory, quality of life, functional activities, presence of depressive symptoms, and caregivers’ burden and cognition. We found a significant difference between self-rated SEF and informant-rated SEF. In 56% of the cases, self-rated SEF was lower than the informant-rated SEF. People with AD mostly (56%) had mildly impaired awareness of disease, 20% had moderate impaired awareness of disease, and 6% were unaware of the disease. A multivariate linear regression examined the association between informant-rated SEF score and the variables. The social functioning and relationship domain of awareness and informant-rated QoL of people with AD were significantly associated with informant-rated SEF. Conclusion: The relationship between informant-rated SEF and awareness of social functioning and relationship supports the multidimensional nature of awareness. SEF and awareness of social functioning shows that they are comprised of judgments related to perceptions about oneself and values qualitatively different from awareness of memory or functionality, which can be directly observed.

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Assessment of Motor and Process Skills as a Measure of IADL Functioning in Pharmacologic Studies of People With Alzheimer's Disease: A Pilot Study

International Psychogeriatrics ◽

10.1017/s1041610297004341 ◽

1997 ◽

Vol 9 (2) ◽

pp. 197-206 ◽

Cited By ~ 22

Author(s):

Frances Oakley ◽

Trey Sunderland

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pilot Study ◽

Motor Skills ◽

Daily Living ◽

Outcome Measure ◽

Process Skills ◽

Drug Trials ◽

Double Blind ◽

Significant Difference

The purpose of this pilot study was to evaluate the usefulness of the Assessment of Motor and Process Skills (AMPS) as an outcome measure of instrumental activities of daily living (IADL) in pharmacologic studies of people with Alzheimer's disease. The AMPS simultaneously measures motor and process skills and their effect on the ability of the person to perform familiar IADL tasks. We administered the AMPS to 11 Alzheimer inpatients in a 31/2-month, double-blind, placebo-controlled, crossover study of fluoxetine and selegiline administered as single agents and in combination with physostigmine. Results indicated that there was a significant difference in IADL ability among study conditions for process skills, but not for motor skills, thereby suggesting that the AMPS is useful as a sensitive outcome measure of IADL ability in drug trials with this population.

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Randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease

Geriatrics and Gerontology International ◽

10.1111/ggi.12696 ◽

2015 ◽

Vol 17 (2) ◽

pp. 211-218 ◽

Cited By ~ 24

Author(s):

Katsutoshi Furukawa ◽

Naoki Tomita ◽

Daisuke Uematsu ◽

Kazunori Okahara ◽

Hiroyuki Shimada ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychiatric Symptoms ◽

Multicenter Trial ◽

Double Blind ◽

Double Blind Placebo

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Interventional Study to Evaluate the Clinical Effects and Safety of the Nutraceutical Compound BrainUp-10® in a Cohort of Patients with Alzheimer’s Disease: A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Trial

Journal of Alzheimer s Disease ◽

10.3233/jad-201501 ◽

2021 ◽

pp. 1-11

Author(s):

Leonardo Guzman-Martinez ◽

Gonzalo A. Farías ◽

José P. Tapia ◽

María P. Sánchez ◽

Patricio Fuentes ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Behavioral Problems ◽

Self Assembly ◽

Controlled Trial ◽

Pilot Trial ◽

Life Quality ◽

Treatment Phase ◽

Clinical Effects ◽

Double Blind

Background: Clinically-evaluated nutraceuticals are candidates for Alzheimer’s disease (AD) prevention and treatment. Phase I studies showed biological safety of the nutraceutical BrainUp-10®, while a pilot trial demonstrated efficacy for treatment. Cell studies demonstrated neuroprotection. BrainUp-10® blocks tau self-assembly. Apathy is the most common of behavioral alterations. Objective: The aim was to explore efficacy of BrainUp-10® in mitigating cognitive and behavioral symptoms and in providing life quality, in a cohort of Chilean patients with mild to moderate AD. Methods: The was a multicenter, randomized, double blind, placebo-controlled phase II clinical study in mild to moderate AD patients treated with BrainUp-10® daily, while controls received a placebo. Primary endpoint was Apathy (AES scale), while secondary endpoints included Mini-Mental State Examination (MMSE), Trail Making Test (TMT A and TMT B), and Neuropsychiatry Index (NPI). AD blood biomarkers were analyzed. Laboratory tests were applied to all subjects. Results: 82 patients were enrolled. The MMSE score improved significantly at week 24 compared to baseline with tendency to increase, which met the pre-defined superiority criteria. NPI scores improved, the same for caregiver distress at 12th week (p = 0.0557), and the alimentary response (p = 0.0333). Apathy tests showed a statistically significant decrease in group treated with BrainUp-10®, with p = 0.0321 at week 4 and p = 0.0480 at week 12 treatment. A marked decrease in homocysteine was shown with BrainUp-10® (p = 0.0222). Conclusion: Data show that BrainUp-10® produces a statistically significant improvement in apathy, ameliorating neuropsychiatric distress of patients. There were no compound-related adverse events. BrainUp-10® technology may enable patients to receive the benefits for their cognitive and behavioral problems.

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Phase II (NAVIGATE-AD study) Results of LY3202626 Effects on Patients with Mild Alzheimer’s Disease Dementia

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-210296 ◽

2021 ◽

pp. 1-16

Author(s):

Albert C. Lo ◽

Cynthia Duggan Evans ◽

Michele Mancini ◽

Hong Wang ◽

Sergey Shcherbinin ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Events ◽

Functional Decline ◽

Neurofibrillary Tangle ◽

Amyloid Β ◽

System Organ Class ◽

Serious Adverse Events ◽

Study Results ◽

Significant Difference

Background: LY3202626 is a small molecule inhibitor of β-site amyloid precursor protein cleaving enzyme (BACE)1 shown to reduce amyloid-β (Aβ)1–40 and Aβ1–42 concentrations in plasma and cerebrospinal fluid developed for the treatment of Alzheimer’s disease (AD). Objective: To assess the change from baseline in flortaucipir positron emission tomography (PET) after treatment with LY3202626 compared with placebo in patients with mild. Methods: Patients received daily 3 mg or 12 mg doses of LY3202626 or placebo for 52 weeks. The primary outcome was assessment of cerebral neurofibrillary tangle load by flortaucipir PET. The study was terminated early following an interim analysis due to a low probability of identifying a statistically significant slowing of cognitive and/or functional decline. Results: A total of 316 patients were randomized and 47 completed the study. There was no statistically significant difference between placebo and either dose of LY3202626 from baseline to 52 weeks, or in annualized change for flortaucipir PET. There was no clinically meaningful difference between placebo and LY3202626 doses on efficacy measures of cognition and function. No deaths or serious adverse events considered related to LY3202626 were reported. A statistically significant increase in treatment-emergent adverse events in the psychiatric disorders system organ class was reported for both LY3202626 doses compared to placebo. Conclusion: LY3202626 tested at doses generating 70–90% BACE inhibition was generally well tolerated in this study. LY3202626 treatment did not result in a clinically significant change in cerebral tau burden as measured by flortaucipir nor in change of functional or cognitive decline compared to placebo.

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Association Between Amygdala Volume and Trajectories of Neuropsychiatric Symptoms in Alzheimer's Disease and Dementia With Lewy Bodies

Frontiers in Neurology ◽

10.3389/fneur.2021.679984 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alberto Jaramillo-Jimenez ◽

Lasse M. Giil ◽

Diego A. Tovar-Rios ◽

Miguel Germán Borda ◽

Daniel Ferreira ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Dementia With Lewy Bodies ◽

Neuropsychiatric Symptoms ◽

Lewy Bodies ◽

Magnetic Resonance Images ◽

Depression Symptoms ◽

Intracranial Volume ◽

Mild Dementia ◽

Amygdala Volume

Introduction: The amygdala is implicated in psychiatric illness. Even as the amygdala undergoes significant atrophy in mild dementia, amygdala volume is underexplored as a risk factor for neuropsychiatric symptoms (NPS).Objective: To analyze the association between baseline amygdala volume and the longitudinal trajectories of NPS and cognitive decline in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) over 5 years.Methods: Eighty-nine patients with mild dementia were included (AD = 55; DLB = 34). Amygdala volume was segmented from structural magnetic resonance images (sMRI) using a semi-automatic method (Freesurfer 6.0) and normalized by intracranial volumes. The intracranial volume-normalized amygdala was used as a predictor of the Neuropsychiatric Inventory (NPI) total score, ordinal NPI item scores (0 = absence of symptoms, 1–3 = mild symptoms, ≥4 = clinically relevant symptoms), and Mini-Mental State Examination (MMSE) as measured annually over 5 years using gamma, ordinal, and linear mixed-effects models, respectively. The models were adjusted for demographic variables, diagnosis, center of sMRI acquisition, and cognitive performance. Multiple testing-corrected p-values (q-values) are reported.Results: Larger intracranial volume-normalized amygdala was associated with less agitation/aggression (odds ratio (OR) = 0.62 [0.43, 0.90], p = 0.011, q = 0.038) and less MMSE decline per year (fixed effect = 0.70, [0.29, 1.03], p = 0.001, q = 0.010) but more depression (OR = 1.49 [1.09, 2.04], p = 0.013, q = 0.040).Conclusions: Greater amygdala volume in mild dementia is associated with lower odds of developing agitation/aggression, but higher odds of developing depression symptoms during the 5-year study period.

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Use of Fast Gamma Magnetic Stimulation Over the Left Prefrontal Dorsolateral Cortex for the Treatment of MCI and Mild Alzheimer's Disease: A Double-Blind, Randomized, Sham-Controlled, Pilot Study

Frontiers in Neurology ◽

10.3389/fneur.2021.729872 ◽

2021 ◽

Vol 12 ◽

Author(s):

Alberto José Mimenza-Alvarado ◽

Sara Gloria Aguilar-Navarro ◽

Francisco M. Martinez-Carrillo ◽

Alma E. Ríos-Ponce ◽

Gabriel Villafuerte

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Effects ◽

Magnetic Stimulation ◽

Controlled Study ◽

Magnetic Pulse ◽

Double Blind ◽

Clinical Trial Registration ◽

Significant Difference ◽

Dorsolateral Cortex

Background: Alzheimer's disease (AD) animal models have shown a reduced gamma power in several brain areas, and induction of these oscillations by non-invasive methods has been shown to modify several pathogenic mechanisms of AD. In humans, the application of low-intensity magnetic fields has shown to be able to produce neural entrainment at the magnetic pulse frequency, making it useful to induce gamma frequencies.Objective: The aim of this study was to assess if the application of fast gamma magnetic stimulation (FGMS) over the left prefrontal dorsolateral cortex would be a safe and well-tolerated intervention that could potentially improve cognitive scores in subjects with mild cognitive impairment and mild AD.Methods: In these randomized, double-blind, sham-controlled study, participants were assigned to either receive daily sessions two times a day of active or sham FGMS for 6 months. Afterward, measurements of adverse effects, cognition, functionality, and depression were taken.Results: Thirty-four patients, 17 in each group, were analyzed for the primary outcome. FGMS was adequately tolerated by most of the subjects. Only four patients from the active FGMS group (23.52%) and one patient from the sham FGMS group (5.88%) presented any kind of adverse effects, showing no significant difference between groups. Nevertheless, FGMS did not significantly change cognitive, functionality, or depressive evaluations.Conclusion: FGMS over the left prefrontal dorsolateral cortex applied twice a day for 6 months resulted to be a viable intervention that can be applied safely directly from home without supervision of a healthcare provider. However, no statistically significant changes in cognitive, functionality, or depression scores compared to sham stimulation were observed.Clinical Trial Registration:www.ClinicalTrials.gov, Identifier: NCT03983655, URL: https://clinicaltrials.gov/ct2/show/NCT03983655.

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Neuropsychiatric Symptoms, Caregiver Burden and Distress in Behavioral-Variant Frontotemporal Dementia and Alzheimer's Disease

Dementia and Geriatric Cognitive Disorders ◽

10.1159/000437351 ◽

2015 ◽

Vol 40 (5-6) ◽

pp. 268-275 ◽

Cited By ~ 32

Author(s):

Thais Bento Lima-Silva ◽

Valéria Santoro Bahia ◽

Viviane Amaral Carvalho ◽

Henrique Cerqueira Guimarães ◽

Paulo Caramelli ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Frontotemporal Dementia ◽

Sex Education ◽

Caregiver Burden ◽

Psychiatric Symptoms ◽

Neuropsychiatric Symptoms ◽

Clinical Dementia Rating ◽

Behavioral Variant Frontotemporal Dementia ◽

Significant Difference

Background/Aims: We aimed to compare caregiver burden and distress in behavioral-variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) and to investigate which factors contribute to caregivers' burden and distress. Methods: Fifty patients and their caregivers were invited to participate. Among the patients, 20 had a diagnosis of bvFTD and 30 had AD. Caregivers and patients were statistically equivalent for age, sex, education and dementia severity according to Clinical Dementia Rating. The protocol included the Short Zarit Burden Inventory, the Neuropsychiatric Inventory (NPI), Disability Assessment for Dementia (DAD), the Cornell Scale for Depression in Dementia (CSDD), Addenbrooke's Cognitive Examination-Revised, the Executive Interview with 25 Items, Direct Assessment of Functional Status and the Geriatric Anxiety Inventory (GAI). Results: In the NPI, caregivers of bvFTD patients reported a higher presence and severity of neuropsychiatric symptoms and caregiver distress compared to caregivers of AD patients. There was no significant difference in the perceived burden. In bvFTD, DAD and GAI scores were significantly correlated with burden, whereas in AD, burden was correlated with CSDD and NPI scores. Psychiatric symptoms were associated with distress in both groups. Conclusions: Caregivers of bvFTD patients experienced higher levels of distress than caregivers of AD patients. Patients' functional limitations were associated with burden of caregivers of bvFTD patients, whereas neuropsychiatric symptoms were associated with caregiver strain in both groups.

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