Jpad-Journal of Prevention of Alzheimers Disease最新文献_第3页

Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects 新型trk受体正变构调节剂ACD856在健康受试者多剂量后的安全性、耐受性、药代动力学和定量脑电图评估

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-07-12 DOI: 10.14283/jpad.2023.89

K. Önnestam, B. Nilsson, M. Rother, E. Rein‐Hedin, J. Bylund, P. Anderer, M. Kemethofer, M. Halldin, J. Sandin, M. Segerdahl

Background ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. Objectives To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. Design This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). Setting The study was conducted at a First-in-Human unit in Sweden. Participants Twenty-four healthy male and female subjects. Intervention The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. Measurements Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. Results Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady stat

{"title":"Safety, Tolerability, Pharmacokinetics and Quantitative Electroencephalography Assessment of ACD856, a Novel Positive Allosteric Modulator of Trk-Receptors Following Multiple Doses in Healthy Subjects","authors":"K. Önnestam, B. Nilsson, M. Rother, E. Rein‐Hedin, J. Bylund, P. Anderer, M. Kemethofer, M. Halldin, J. Sandin, M. Segerdahl","doi":"10.14283/jpad.2023.89","DOIUrl":"https://doi.org/10.14283/jpad.2023.89","url":null,"abstract":"Background ACD856 is a positive allosteric modulator of tropomyosin receptor kinase (Trk) receptors which has shown to have pro-cognitive and anti-depressant-like effects in various animal models. It is currently in clinical development for the treatment of Alzheimer’s disease and other disorders where cognition is impaired and is also considered for indications such as depression or other neuropsychiatric diseases. ACD856 has a novel mechanism of action modulating the activity of the Trk-receptors, resulting in increased stimulation of the neurotrophin signaling pathways. Previous studies applying single intravenous and oral doses of ACD856 indicate that ACD856 is safe and well-tolerated by healthy volunteer subjects, and that it has suitable safety and pharmacokinetic properties for further clinical development. Objectives To investigate the safety and tolerability of 7 days of treatment with multiple ascending oral doses of ACD856 in healthy subjects, and to characterize its pharmacokinetic (PK) properties. In addition, pharmacodynamic effects of ACD856 using quantitative electroencephalography (qEEG) as an indicator for central target engagement were assessed. Design This was a prospective, phase I, double-blind, parallel-group, placebo-controlled, randomized study of the safety, tolerability, PK and pharmacodynamics of multiple ascending oral doses of ACD856 in healthy subjects. ACD856 or placebo were administered in 3 ascending dose cohorts of 8 subjects. Within each cohort, subjects were randomized to receive either ACD856 (n=6) or placebo (n=2). Setting The study was conducted at a First-in-Human unit in Sweden. Participants Twenty-four healthy male and female subjects. Intervention The study medication was administered as an oral solution, with ACD856 or the same contents without the active ingredient (placebo). The dose levels ranged from 10 mg to 90 mg. ACD856 was administered once daily for 7 days, targeting steady state. Measurements Safety and tolerability assessments included adverse events, laboratory, vital signs, 12-lead electrocardiogram (ECG), physical examination, assessment of stool frequency and questionnaires to assess symptoms of anxiety, depression, as well as suicidal ideation and behavior. In addition, cardiodynamic ECGs were extracted to evaluate cardiac safety. PK parameters were calculated based on measured concentrations of ACD856 in plasma, urine, and cerebrospinal fluid (CSF) samples. Metabolite profiling, characterization and analysis was performed based on and urine samples. qEEG was recorded for patients in the two highest dose cohorts (30 and 90 mg/day) as a pharmacodynamic assessment to explore central target engagement. Results Treatment with ACD856 was well tolerated with no serious adverse events. No treatment emergent or dose related trends were observed for any of the safety assessments. ACD856 was rapidly absorbed and reached maximum plasma exposure at 30 to 45 minutes after administration. Steady stat","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"778-789"},"PeriodicalIF":6.4,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Preferences about Future Alzheimer’s Disease Treatments Elicited through an Online Survey Using the Threshold Technique 通过使用阈值技术的在线调查对未来阿尔茨海默病治疗的偏好

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-06-30 DOI: 10.14283/jpad.2023.84

Sonia Roldan Munoz, S. T. de Vries, G. Lankester, F. Pignatti, B. C. van Munster, I. Radford, L. Guizzaro, P. G. M. Mol, H. Hillege, D. Postmus

Treatments aiming at slowing down the progression of Alzheimer’s disease (AD) may soon become available. However, information about the risks that people are willing to accept in order to delay the progression of the disease is limited. To determine the trade-offs that individuals are willing to make between the benefits and risks of hypothetical treatments for AD, and the extent to which these trade-offs depend on individuals’ characteristics and beliefs about medicines. Online, cross-sectional survey study. Population in the UK. Public link to the survey available at the websites of Alzheimer’s Research UK and Join Dementia Research. Everyone self-reported ≥18 years old was eligible to participate. A total of 4384 people entered the survey and 3658 completed it. The maximum acceptable risks (MARs) of participants for moderate and severe adverse events in exchange for a 2-year delay in disease progression. The risks were expressed on ordinal scales, from <10% to ≥50%, above a pre-existing risk of 30% for moderate adverse events and 10% for severe adverse events. We obtained the population median MARs using log-normal survival models and quantified the effects of individuals’ characteristics and beliefs about medicines in terms of acceleration factors. For the moderate adverse events, 26% of the participants had a MAR ≥50%, followed by 25% of the participants with a MAR of 10 to <20%, giving an estimated median MAR of 25.4% (95% confidence interval [CI] 24.5 to 26.3). For the severe adverse events, 43% of the participants had a MAR <10%, followed by 25% of the participants with a MAR of 10 to <20%, resulting in an estimated median MAR of 12.1% (95%CI 11.6 to 12.5). Factors that were associated with the individuals’ MARs for one or both adverse events were age, gender, educational level, living alone, and beliefs about medicines. Whether or not individuals were living with memory problems or had experience as a caregiver had no effect on the MARs for any of the adverse events. Trade-offs between benefits and risks of AD treatments are heterogeneous and influenced by individuals’ characteristics and beliefs about medicines. This heterogeneity should be acknowledged during the medicinal product decision-making in order to fulfil the needs of the various subpopulations.

旨在减缓阿尔茨海默病(AD)进展的治疗方法可能很快就会出现。然而，人们为了延缓疾病进展而愿意接受的风险信息是有限的。确定个人愿意在AD假设治疗的益处和风险之间做出的权衡，以及这些权衡在多大程度上取决于个人的特征和对药物的信念。在线，横断面调查研究。英国的人口。在英国阿尔茨海默氏症研究和加入痴呆症研究的网站上可以找到调查的公共链接。所有自我报告≥18岁的人都有资格参加。共有4384人参与调查，3658人完成了调查。参与者发生中度和重度不良事件的最大可接受风险(MARs)，以换取2年的疾病进展延迟。风险以顺序量表表示，从<10%到≥50%，高于中度不良事件存在的30%和严重不良事件存在的10%的风险。我们使用对数正态生存模型获得了人群中位MARs，并根据加速因子量化了个体特征和对药物的信念的影响。对于中度不良事件，26%的参与者的MAR≥50%，其次是25%的参与者，MAR为10至<20%，估计MAR中位数为25.4%(95%置信区间[CI] 24.5至26.3)。对于严重不良事件，43%的参与者的MAR <10%，其次是25%的参与者，MAR为10至<20%，导致估计中位MAR为12.1% (95%CI 11.6至12.5)。与个人不良事件MARs相关的因素有年龄、性别、教育水平、独居和对药物的信念。无论个人是否有记忆问题或是否有过照顾者的经历，对MARs的任何不良事件都没有影响。阿尔茨海默病治疗的益处和风险之间的权衡是异质的，并受到个体特征和对药物的信念的影响。在药品决策过程中应承认这种异质性，以满足不同亚群的需求。

{"title":"Preferences about Future Alzheimer’s Disease Treatments Elicited through an Online Survey Using the Threshold Technique","authors":"Sonia Roldan Munoz, S. T. de Vries, G. Lankester, F. Pignatti, B. C. van Munster, I. Radford, L. Guizzaro, P. G. M. Mol, H. Hillege, D. Postmus","doi":"10.14283/jpad.2023.84","DOIUrl":"https://doi.org/10.14283/jpad.2023.84","url":null,"abstract":"Treatments aiming at slowing down the progression of Alzheimer’s disease (AD) may soon become available. However, information about the risks that people are willing to accept in order to delay the progression of the disease is limited. To determine the trade-offs that individuals are willing to make between the benefits and risks of hypothetical treatments for AD, and the extent to which these trade-offs depend on individuals’ characteristics and beliefs about medicines. Online, cross-sectional survey study. Population in the UK. Public link to the survey available at the websites of Alzheimer’s Research UK and Join Dementia Research. Everyone self-reported ≥18 years old was eligible to participate. A total of 4384 people entered the survey and 3658 completed it. The maximum acceptable risks (MARs) of participants for moderate and severe adverse events in exchange for a 2-year delay in disease progression. The risks were expressed on ordinal scales, from <10% to ≥50%, above a pre-existing risk of 30% for moderate adverse events and 10% for severe adverse events. We obtained the population median MARs using log-normal survival models and quantified the effects of individuals’ characteristics and beliefs about medicines in terms of acceleration factors. For the moderate adverse events, 26% of the participants had a MAR ≥50%, followed by 25% of the participants with a MAR of 10 to <20%, giving an estimated median MAR of 25.4% (95% confidence interval [CI] 24.5 to 26.3). For the severe adverse events, 43% of the participants had a MAR <10%, followed by 25% of the participants with a MAR of 10 to <20%, resulting in an estimated median MAR of 12.1% (95%CI 11.6 to 12.5). Factors that were associated with the individuals’ MARs for one or both adverse events were age, gender, educational level, living alone, and beliefs about medicines. Whether or not individuals were living with memory problems or had experience as a caregiver had no effect on the MARs for any of the adverse events. Trade-offs between benefits and risks of AD treatments are heterogeneous and influenced by individuals’ characteristics and beliefs about medicines. This heterogeneity should be acknowledged during the medicinal product decision-making in order to fulfil the needs of the various subpopulations.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"756 - 764"},"PeriodicalIF":6.4,"publicationDate":"2023-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reducing the Effects of Ageing on Cognition with Therapeutic Intervention of an Oral Multi-Nutrient: The REACTION Pilot Trial Study Design 口服多种营养素治疗干预减少衰老对认知的影响:反应试验研究设计

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-06-19 DOI: 10.14283/jpad.2023.81

Christian J. Camargo, S. Merritt, M. Modjeski, D. S. Counotte, K. Fernández McInerney

Clinical benefits have been reported with a specific multinutrient intervention (Souvenaid) in Alzheimer’s disease and mild cognitive impairment due to Alzheimer’s disease. The effects of Souvenaid in age-related cognitive decline are not established. To assess the feasibility of using virtual assessments to study the effects of a multinutrient on cognitive ageing. This is a randomized, double-blind, placebo-controlled, parallel group virtual pilot trial performed over 6 months in a single-centre. Participants are randomly allocated (1:1) to receive the specific multinutrient (Souvenaid) or an isocaloric, same tasting, placebo. Trial visits are done virtually using secure online video communication. English or Spanish speaking people aged 55–89 years from all ethnic groups and considered to have age-related cognitive decline are eligible. Neuropyschological tests are done at baseline and after 6 months of intervention. Participants are contacted monthly by telephone to monitor safety, assess motivation and promote compliance. The primary outcome is feasibility determined by assessing recruitment rate, recruitment time, adherence rate and retention rate. A comprehensive set of neuropyschological measures will provide a broad assessment of cognitive function, including verbal memory, processing speed, and attention and executive function. Self-reported questionnaires are used to assess quality of life. This pilot trial will provide data to guide inform selection of participants and outcome measures in future studies in age-related cognitive decline.

据报道，针对阿尔茨海默病和阿尔茨海默病引起的轻度认知障碍，采用特定的多营养素干预(Souvenaid)可获得临床益处。苏维尼在与年龄相关的认知衰退中的作用尚未确定。评估使用虚拟评估来研究多种营养素对认知老化的影响的可行性。这是一项随机、双盲、安慰剂对照、平行组虚拟试点试验，在单中心进行了6个月以上。参与者被随机分配(1:1)，接受特定的多营养素(Souvenaid)或等热量、相同味道的安慰剂。试用访问使用安全的在线视频通信进行虚拟。年龄在55-89岁之间、说英语或西班牙语且被认为有与年龄相关的认知能力下降的所有种族的人都符合条件。在基线和干预6个月后进行神经心理学测试。参与者每月通过电话联系，以监督安全，评估动机和促进遵守。主要结局是通过评估招募率、招募时间、依从率和保留率来确定可行性。一套全面的神经心理学测量将提供认知功能的广泛评估，包括言语记忆、处理速度、注意力和执行功能。自我报告问卷用于评估生活质量。该试点试验将提供数据，以指导未来年龄相关认知衰退研究的参与者选择和结果测量。

{"title":"Reducing the Effects of Ageing on Cognition with Therapeutic Intervention of an Oral Multi-Nutrient: The REACTION Pilot Trial Study Design","authors":"Christian J. Camargo, S. Merritt, M. Modjeski, D. S. Counotte, K. Fernández McInerney","doi":"10.14283/jpad.2023.81","DOIUrl":"https://doi.org/10.14283/jpad.2023.81","url":null,"abstract":"Clinical benefits have been reported with a specific multinutrient intervention (Souvenaid) in Alzheimer’s disease and mild cognitive impairment due to Alzheimer’s disease. The effects of Souvenaid in age-related cognitive decline are not established. To assess the feasibility of using virtual assessments to study the effects of a multinutrient on cognitive ageing. This is a randomized, double-blind, placebo-controlled, parallel group virtual pilot trial performed over 6 months in a single-centre. Participants are randomly allocated (1:1) to receive the specific multinutrient (Souvenaid) or an isocaloric, same tasting, placebo. Trial visits are done virtually using secure online video communication. English or Spanish speaking people aged 55–89 years from all ethnic groups and considered to have age-related cognitive decline are eligible. Neuropyschological tests are done at baseline and after 6 months of intervention. Participants are contacted monthly by telephone to monitor safety, assess motivation and promote compliance. The primary outcome is feasibility determined by assessing recruitment rate, recruitment time, adherence rate and retention rate. A comprehensive set of neuropyschological measures will provide a broad assessment of cognitive function, including verbal memory, processing speed, and attention and executive function. Self-reported questionnaires are used to assess quality of life. This pilot trial will provide data to guide inform selection of participants and outcome measures in future studies in age-related cognitive decline.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"821 - 827"},"PeriodicalIF":6.4,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Editorial: Dietary Cholesterol and Dementia Risk. 社论：膳食胆固醇与痴呆症风险。

IF 8.5 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.66

L T Middleton, E Riboli

引用次数: 0

Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia. PreventE4的基线发现：一项双盲安慰剂对照临床试验，在痴呆症发作前测试APOE4携带者的高剂量DHA。

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.77

H N Yassine, I C Arellanes, A Mazmanian, L De La Cruz, J Martinez, L Contreras, N Kono, B S Liu, D Badie, M A Bantugan, A Grindon, T Urich, L D'Orazio, B A Emmanuel, H C Chui, W J Mack, M G Harrington, M N Braskie, L S Schneider

Introduction: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.

Methods: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.

Results: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).

Conclusions: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.

引言：血液中ω-3多不饱和脂肪酸二十二碳六烯酸（DHA）水平较低与认知功能较差有关，尤其是在APOEε4携带者中。在临床痴呆发作前开始补充DHA是否能延缓或减缓疾病进展尚不清楚。方法：PreventE4是一项双盲、单点、随机、安慰剂对照试验，针对具有有限ω-3摄入量和痴呆风险因素的认知未受损个体（n=368）。其目的是确定（1）携带APOEε4等位基因是否与DHA向大脑的输送减少有关；以及（2）高剂量补充DHA是否影响AD的脑成像生物标志物和认知功能。结果：365名55岁至80岁（平均年龄66岁）的认知障碍患者被随机分配到每天2克DHA或相同外观的安慰剂中，为期2年。一半的参与者被要求在基线和6个月的访视中完成腰椎穿刺，以获得脑脊液（CSF）。主要的试验结果指标是干预6个月后CSF DHA与花生四烯酸比率的变化（n=181）。次要试验结果包括在24个月时使用静息状态功能MRI的功能和结构连接的变化（n=365）。探索性结果包括24个月时（n=365）神经心理状态评估的可重复电池组的变化。结论：PreventE4的研究结果将阐明携带APOEε4等位基因的个体大脑中DHA的输送，并对痴呆预防策略产生影响。试验注册号为NCT03613844。

{"title":"Baseline Findings of PreventE4: A Double-Blind Placebo Controlled Clinical Trial Testing High Dose DHA in APOE4 Carriers before the Onset of Dementia.","authors":"H N Yassine, I C Arellanes, A Mazmanian, L De La Cruz, J Martinez, L Contreras, N Kono, B S Liu, D Badie, M A Bantugan, A Grindon, T Urich, L D'Orazio, B A Emmanuel, H C Chui, W J Mack, M G Harrington, M N Braskie, L S Schneider","doi":"10.14283/jpad.2023.77","DOIUrl":"10.14283/jpad.2023.77","url":null,"abstract":"Introduction: Lower blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) are correlated with worse cognitive functions, particularly among APOE ε4 carriers. Whether DHA supplementation in APOE ε4 carriers with limited DHA consumption and dementia risk factors can delay or slow down disease progression when started before the onset of clinical dementia is not known.Methods: PreventE4 is a double-blind, single site, randomized, placebo-controlled trial in cognitively unimpaired individuals with limited omega-3 consumption and dementia risk factors (n=368). Its objectives are to determine (1) whether carrying the APOE ε4 allele is associated with lower delivery of DHA to the brain; and (2) whether high dose DHA supplementation affects brain imaging biomarkers of AD and cognitive function.Results: 365 cognitively unimpaired individuals between 55 and 80 (mean age 66) were randomized to 2 grams of DHA per day or identically appearing placebo for a period of 2 years. Half the participants were asked to complete lumbar punctures at baseline and 6-month visits to obtain cerebrospinal fluid (CSF). The primary trial outcome measure is the change in CSF DHA to arachidonic acid ratio after 6 months of the intervention (n=181). Secondary trial outcomes include the change in functional and structural connectivity using resting state functional MRI at 24 months (n=365). Exploratory outcomes include the change in Repeatable Battery of the Assessment of Neuropsychological Status at 24 months (n=365).Conclusions: Findings from PreventE4 will clarify the brain delivery of DHA in individuals carrying the APOE ε4 allele with implications for dementia prevention strategies. Trial was registered as NCT03613844.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"810-820"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease. s -腺苷蛋氨酸在阿尔茨海默病引起的轻度认知障碍或痴呆患者中的II期随机、多中心、双盲、安慰剂对照试验方案

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.55

S Holper, R Watson, L Churilov, P Yates, Y Y Lim, K J Barnham, N Yassi

S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer’s disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation. The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD. This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care. The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation. Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.

背景s -腺苷蛋氨酸(SAMe)是神经元稳态所需的多种途径中的关键代谢物，其中一些途径在阿尔茨海默病(AD)中受损。纠正AD大脑特有的SAMe缺陷可能会减弱或阻止驱动AD相关神经变性的病理过程，包括异常的tau过度磷酸化和DNA低甲基化。本研究的主要目的是验证一种假设，即与安慰剂相比，在AD引起的轻度认知障碍或痴呆患者中，每天口服400 mg SAMe治疗180天将导致血浆p-tau181水平从基线水平更大幅度降低。这是一项II期、随机、多中心、双盲、安慰剂对照试验，共有60名阿尔茨海默氏症患者患有轻度认知障碍或痴呆。参与者将以1:1的比例随机接受SAMe或匹配的安慰剂，作为AD标准治疗的辅助治疗。主要结果是血浆p-tau181浓度在基线和治疗后180天的变化，将在活性组和安慰剂组之间进行比较。次要结果是SAMe给药的安全性(严重不良事件的发生率)，认知能力从基线的变化(通过神经心理状态评估的可重复电池测量)，以及DNA甲基化的表观遗传变化。结论:SAMe在II期试验中有效、安全地降低血浆p-tau181，将为令人兴奋的转化研究领域和更大规模的III期试验铺平道路。本文的在线版本为10.14283/jpad.2023.55。

{"title":"Protocol of a Phase II Randomized, Multi-Center, Double-Blind, Placebo-Controlled Trial of S-Adenosyl Methionine in Participants with Mild Cognitive Impairment or Dementia Due to Alzheimer's Disease.","authors":"S Holper, R Watson, L Churilov, P Yates, Y Y Lim, K J Barnham, N Yassi","doi":"10.14283/jpad.2023.55","DOIUrl":"10.14283/jpad.2023.55","url":null,"abstract":"S-adenosyl methionine (SAMe) is a pivotal metabolite in multiple pathways required for neuronal homeostasis, several of which are compromised in Alzheimer’s disease (AD). Correction of the SAMe deficiency that is characteristic of the AD brain may attenuate or prevent pathological processes driving AD-associated neurodegeneration including aberrant tau hyperphosphorylation and DNA hypomethylation. The primary aim is to test the hypothesis that daily treatment with 400 mg oral SAMe for 180 days will lead to a greater reduction from baseline in plasma levels of p-tau181 compared to placebo in patients with mild cognitive impairment or dementia due to AD. This is a phase II, randomized, multi-center, double-blind, placebo-controlled trial among 60 participants with mild cognitive impairment or dementia due to AD. Participants will be randomized in a 1:1 ratio to receive either SAMe or matching placebo, to be taken as an adjunct to their AD standard of care. The primary outcome is change in plasma p-tau181 concentration between baseline and following 180 days of treatment, which will be compared between the active and placebo group. Secondary outcomes are the safety of SAMe administration (incidence of serious adverse events), change from baseline in cognitive performance (as measured by the Repeatable Battery for the Assessment of Neuropsychological Status), and epigenetic changes in DNA methylation. Demonstration of effective and safe lowering of plasma p-tau181 with SAMe in this phase II trial would pave the way for an exciting field of translational research and a larger phase III trial.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"800-809"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10186290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47271564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Plasma Oligomer β-Amyloid and White Matter Microstructural Integrity in Cognitively Normal Older Adults According to Cerebral Amyloid Deposition. 根据脑淀粉样蛋白沉积，认知正常老年人血浆寡聚体β-淀粉样蛋白和白质微结构完整性。

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.87

Sheng-Min Wang, Dong Woo Kang, Yoo Hyun Um, Sunghwan Kim, Chang Uk Lee, Philip Scheltens, Hyun Kook Lim

Background: Multimer detection system-oligomeric amyloid-β (MDS-OAβ) measure plasma OAβ level, which is associated with earlier Alzheimer's disease (AD) pathology. However, no study has investigated MDS-OAβ differences in cognitive normal older adults (CN) with or without cerebral Aβ burden and its correlation with Aβ deposition and white matter (WM) integrity.

Objective: To investigate associations among cerebral Aβ burden, MDS-OAβ, and WM integrity in CN.

Design: This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database.

Setting: CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, between 2017 and 2022.

Participants: A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included.

Measurements: Plasma Aβ level using MDS-OAβ, cerebral Aβ deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized.

Restuls: The amyloid-PET positive group showed higher MDS-OAβ level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAβ positive group showed higher global cerebral Aβ deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAβ negative group. MDS-OAβ was positively associated with global cerebral Aβ deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity.

Conclusions: In this study, MDS-OAβ value demonstrated earlier and different AD pathology than cerebral Aβ retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAβ and cerebral Aβ with WM integrity disturbance and cortical atrophy during the AD trajectory.

背景：多模式检测系统寡聚淀粉样蛋白-β（MDS-OAβ）测量血浆OAβ水平，这与早期阿尔茨海默病（AD）病理有关。然而，没有研究调查有或没有大脑Aβ负荷的认知正常老年人（CN）的MDS-OAβ差异及其与Aβ沉积和白质（WM）完整性的相关性。目的：研究CN患者大脑Aβ负荷、MDS-OAβ和WM完整性之间的关系。设计：这是一项单中心、横断面研究，使用了天主教老龄化脑成像（CABI）数据库的数据。设置：CABI数据库包含2017年至2022年间在韩国天主教大学汝矣岛圣玛丽医院天主教脑健康中心门诊就诊的患者的脑部扫描。参与者：共包括34例淀粉样蛋白PET阴性CN和23例淀粉样肽PET阳性CN。测量：使用MDS-OAβ的血浆Aβ水平，使用全局标准化摄取值比率（SUVR）值的大脑Aβ沉积水平，使用分数各向异性（FA）和平均扩散率（MD）的WM完整性，以及结构MRI的皮层厚度。Restuls:淀粉样蛋白PET阳性组的MDS-OAβ水平高于淀粉样蛋白阴性组（0.997±0.19 vs.0.79±0.28，P结论：在本研究中，根据淀粉样蛋白PET，MDS-OAβ值显示出比大脑Aβ滞留更早且不同的AD病理。需要进行纵向研究来阐明AD轨迹中血浆OAβ和大脑Aβ与WM完整性紊乱和皮质萎缩的因果关系。

{"title":"Plasma Oligomer β-Amyloid and White Matter Microstructural Integrity in Cognitively Normal Older Adults According to Cerebral Amyloid Deposition.","authors":"Sheng-Min Wang, Dong Woo Kang, Yoo Hyun Um, Sunghwan Kim, Chang Uk Lee, Philip Scheltens, Hyun Kook Lim","doi":"10.14283/jpad.2023.87","DOIUrl":"10.14283/jpad.2023.87","url":null,"abstract":"Background: Multimer detection system-oligomeric amyloid-β (MDS-OAβ) measure plasma OAβ level, which is associated with earlier Alzheimer's disease (AD) pathology. However, no study has investigated MDS-OAβ differences in cognitive normal older adults (CN) with or without cerebral Aβ burden and its correlation with Aβ deposition and white matter (WM) integrity.Objective: To investigate associations among cerebral Aβ burden, MDS-OAβ, and WM integrity in CN.Design: This is a single center, cross-sectional study which used data from Catholic Aging Brain Imaging (CABI) database.Setting: CABI database contains brain scans of patients who visited the outpatient clinic at Catholic Brain Health Center, Yeouido St. Mary's Hospital, The Catholic University of Korea, between 2017 and 2022.Participants: A total 34 amyloid-PET negative CN and 23 amyloid-PET positive CN were included.Measurements: Plasma Aβ level using MDS-OAβ, cerebral Aβ deposition level using global standardized uptake value ratio (SUVR) values, WM integrity using fractional anisotropy (FA) and mean diffusivity (MD), and cortical thickness from structural MRI were utilized.Restuls: The amyloid-PET positive group showed higher MDS-OAβ level than the amyloid-PET negative group (0.997 ± 0.19 vs. 0.79 ± 0.28, P <0.005), but they did not differ in WM integrity or cortical thickness. The MDS-OAβ positive group showed higher global cerebral Aβ deposition or mean global SUVR values (0.609 ± 0.135 vs. 0.533 ± 0.121 vs. P <0.05), lower regional FA of left forceps minor and the right superior longitudinal fasciculus (family-wise error rate, p <0.05), and lower cortical thickness of left fusiform (p <0.05, Monte Carlo simulation) than the MDS-OAβ negative group. MDS-OAβ was positively associated with global cerebral Aβ deposition (r=0.278, P <0.05) and negatively associated (r = - 0.324, P < 0.05) with regional WM integrity.Conclusions: In this study, MDS-OAβ value demonstrated earlier and different AD pathology than cerebral Aβ retention according to amyloid-PET. Longitudinal studies are needed to elucidate the causal relationships of plasma OAβ and cerebral Aβ with WM integrity disturbance and cortical atrophy during the AD trajectory.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"837-846"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Social Determinants of Health among Older Adults with Dementia in Urban and Rural Areas. 影响城乡老年痴呆患者健康的社会决定因素

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.1007/s42414-023-0002-2

M M Bartley, H Baer-Benson, D R Schroeder, J L St Sauver, N Khera, J M Griffin

Background: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia.

Objectives: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia.

Design: Descriptive study.

Setting/participants: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included.

Measurements: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes.

Results: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003).

Conclusion: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.

背景：健康的社会决定因素（SDOH）可能影响痴呆症患者的健康。人们对城市和农村痴呆症患者的SDOH差异知之甚少。目的：探讨轻度认知障碍（MCI）和痴呆患者SDOH的城乡差异。设计：描述性研究。设置/参与者：包括在2019年6月1日至2021年6月30日期间在梅奥诊所（美国明尼苏达州罗切斯特市）接受社区内科治疗并完成SDOH问题的≥55岁MCI或痴呆症患者。测量：SDOH问题涉及教育、抑郁、饮酒、经济压力、粮食不安全、体育活动、社会关系、压力和交通。SDOH数据根据城乡通勤地区代码按位置进行比较。结果：在3552名MCI（n=1495）或痴呆症（n=2057）患者中，62%生活在城市地区，19%生活在大农村，10%生活在小农村，9%生活在偏远地区。大约60%的人身体不活跃，20%的人社交孤立，30%的人有压力问题。农村患者经历了更大的经济压力（p=0.003）。结论：在城市和农村地区的MCI和痴呆症患者中，社交孤立、压力和身体不活动很常见。改善身心健康的有针对性的干预措施可能对这一人群产生重大影响。

{"title":"Social Determinants of Health among Older Adults with Dementia in Urban and Rural Areas.","authors":"M M Bartley, H Baer-Benson, D R Schroeder, J L St Sauver, N Khera, J M Griffin","doi":"10.1007/s42414-023-0002-2","DOIUrl":"10.1007/s42414-023-0002-2","url":null,"abstract":"Background: Social determinants of health (SDOH) may influence health in people living with dementia. Little is known about SDOH differences in urban compared to rural dwelling people living with dementia.Objectives: To explore urban-rural differences in SDOH in people living with mild cognitive impairment (MCI) and dementia.Design: Descriptive study.Setting/participants: People ≥55 years with MCI or dementia empaneled to Community Internal Medicine at Mayo Clinic (Rochester, MN, USA) who completed SDOH questions between June 1, 2019 and June 30, 2021 were included.Measurements: SDOH questions addressed education, depression, alcohol use, financial strain, food insecurity, physical activity, social connections, stress and transportation. SDOH data were compared by location based on Rural-Urban Commuting Areas Codes.Results: Of 3552 persons with MCI (n=1495) or dementia (n=2057), 62% lived in urban areas, 19% in large rural, 10% in small rural and 9% in isolated areas. Approximately 60% were physically inactive, 20% socially isolated and 30% had stress concerns. Rural patients experienced greater financial strain (p=0.003).Conclusion: Social isolation, stress and physical inactivity are common in people living with MCI and dementia across urban and rural areas. Targeted interventions to improve physical and psychosocial health could have great impact in this population.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"1 1","pages":"895-902"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45013586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study. TOMM40'523 变异和 APOE 对 4 年认知纵向变化的基因型影响：TOMMORROW研究

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.115

H Zou, S Luo, H Liu, M W Lutz, D A Bennett, B L Plassman, K A Welsh-Bohmer

Background: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD.

Objectives: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance.

Design: A phase 3, double-blind, placebo-controlled, randomized clinical trial.

Setting: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.

Participants: Cognitively normal older adults aged 65 to 83.

Intervention: Pioglitazone tablet.

Measurements: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes.

Results: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers.

Conclusions: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

背景：据报道，TOMM40的523多T长度多态性（rs10524523）会影响APOE ε3/3携带者的纵向认知测试表现。之前的研究结果并不一致。目前还不清楚特定的APOE和TOMM40基因型是否会导致AD临床前阶段纵向认知表现的异质性：为了确定这些基因对早期AD临床前阶段纵向认知变化的影响，我们利用最近结束的TOMMORROW研究中的临床试验数据，考察了APOE和TOMM40基因型对神经心理学测试表现的影响：3期双盲安慰剂对照随机临床试验：地点：澳大利亚、德国、瑞士、英国和美国的学术附属机构和私人研究诊所：干预措施：吡格列酮片剂：干预措施：吡格列酮片剂：TOMMORROW试验的参与者根据APOE基因型（APOE ε3/3、APOE ε3/4、APOE ε4/4）进行分层。APOE ε3/3携带者按TOMM40'523基因型进一步分层。最终分析数据集包括 1,330 名 APOE ε3/3 携带者和 7,001 次就诊。线性混合模型用于比较不同APOE组和不同TOMM40'523基因型的APOE ε3/3携带者的认知能力下降率：APOE ε3/4和APOE ε4/4基因型与APOE ε3/3基因型相比，在整体认知、外显记忆和语言表达方面的表现更差。此外，在四年的观察中，与带有TOMM40'523-S/VL和VL/VL基因型的APOE ε3/3携带者相比，带有TOMM40'523-S/S基因型的APOE ε3/3携带者与带有TOMM40'523-S/VL和VL/VL基因型的APOE ε3/4和APOE ε4/4携带者相比，在总体认知、执行功能和注意力处理测试中表现出更好的总体认知能力和更快的认知能力下降速度：结论：我们认为，APOE和TOMM40基因型可能会单独导致AD前MCI阶段的认知异质性。在临床试验中，控制这种基因变异性对于减缓认知能力下降的速度和/或预防临床前AD症状的出现非常重要。

{"title":"Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.","authors":"H Zou, S Luo, H Liu, M W Lutz, D A Bennett, B L Plassman, K A Welsh-Bohmer","doi":"10.14283/jpad.2023.115","DOIUrl":"10.14283/jpad.2023.115","url":null,"abstract":"Background: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD.Objectives: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance.Design: A phase 3, double-blind, placebo-controlled, randomized clinical trial.Setting: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA.Participants: Cognitively normal older adults aged 65 to 83.Intervention: Pioglitazone tablet.Measurements: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes.Results: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers.Conclusions: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"886-894"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10734664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66893765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding Barriers and Facilitators to Signing Up for a Mobile-Responsive Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer's Disease Prevention Studies. 了解注册移动响应登记处招募健康志愿者和代表性不足社区成员进行阿尔茨海默病预防研究的障碍和推动者。

IF 6.4 3区医学 Q1 CLINICAL NEUROLOGY

Jpad-Journal of Prevention of Alzheimers Disease

Pub Date : 2023-01-01 DOI: 10.14283/jpad.2023.67

D Neffa-Creech, R Aggarwal, C Stowell, U Menon, S George, A Plant, J B Langbaum

Background: Alzheimer's disease (AD) disproportionately affects Black/African American and Hispanic/Latino adults, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings.Objectives: This study explores barriers and facilitators to signing up for an AD participant recruitment registry website intended to optimize recruitment of these adults. The registry is geared toward recruitment on smartphones and tablets (mobile devices), as research suggests that mobile-first approaches may be more successful within these populations.Design: In 2020, we conducted four focus groups (n = 39) and an online survey (n = 1010) with Black/African American and Hispanic/Latino adults. The survey also included Whites as a comparison group.Setting: Focus groups were in-person at research facilities in New Orleans, Louisiana, and Los Angeles, California. The online survey was distributed by a survey panel company to participants nationwide.Participants: Black/African American (n = 360), Hispanic/Latino (n = 359), or White (n = 330) individuals, 45-75 years old, who self-reported not having mild cognitive impairment (MCI), dementia, or AD.Measurements: Barriers and facilitators explored in the focus groups and survey were related to health and AD (e.g., AD-related concerns and past participation/willingness to participate in health or AD studies); current use of mobile devices (e.g., comfort using devices and receptivity to the AD recruitment registry); and participant characteristics and beliefs (e.g., demographics, health literacy level, and trust in government and the scientific community).Results: The focus groups and survey revealed similar findings. Participants commonly use mobile devices to go online and perform health-related activities. They were aware of AD, expressed concerns with developing it, and were willing to participate in AD-related studies (motivated by personal connection to AD, altruism, and compensation). When presented with the AD recruitment registry, most provided positive feedback (e.g., easy to use and informative) and shared an interest in joining. Barriers to joining the registry with a mobile device included complex or multistep enrollment processes, beliefs that studies are primarily for those with a specific disease, and confusion about how studies can prevent AD among those low-risk for AD. The focus groups also revealed that Black/African American participants expressed more hesitation than Hispanic/Latinos in joining the registry due to greater distrust in the government and scientific community.Conclusions: Recruiting more Black/African American and Hispanic/Latino participants into AD studies is vitally important. This mixed methods study suggests that adults in these underrepres

背景：阿尔茨海默病（AD）不成比例地影响黑人/非裔美国人和西班牙裔/拉丁裔成年人，但他们在AD研究中的代表性不足。这些人群面临的招聘挑战限制了调查结果的可推广性。目的：本研究探讨了注册AD参与者招聘注册网站的障碍和促进因素，该网站旨在优化这些成年人的招聘。该注册旨在通过智能手机和平板电脑（移动设备）进行招聘，因为研究表明，移动优先的方法在这些人群中可能更成功。设计：2020年，我们对黑人/非裔美国人和西班牙裔/拉丁裔成年人进行了四个焦点小组（n=39）和一项在线调查（n=1010）。调查还将白人作为对照组。背景：焦点小组在路易斯安那州新奥尔良和加利福尼亚州洛杉矶的研究机构进行了现场交流。这项在线调查由一家调查小组公司分发给全国各地的参与者。参与者：黑人/非裔美国人（n=360）、西班牙裔/拉丁裔（n=359）或白人（n=330），45-75岁，自我报告没有轻度认知障碍（MCI）、痴呆症、，或AD。测量：焦点小组和调查中探讨的障碍和促进者与健康和AD有关（例如，AD相关的问题和过去参与/愿意参与健康或AD研究）；移动设备的当前使用情况（例如，使用设备的舒适度和对AD招募注册表的接受度）；以及参与者的特征和信仰（例如，人口统计、健康知识水平以及对政府和科学界的信任）。结果：焦点小组和调查结果相似。参与者通常使用移动设备上网并进行与健康相关的活动。他们意识到AD，对开发AD表示担忧，并愿意参与AD相关研究（动机是与AD的个人联系、利他主义和补偿）。当向AD招聘登记处介绍时，大多数人都提供了积极的反馈（例如，易于使用和信息丰富），并对加入感兴趣。使用移动设备加入注册中心的障碍包括复杂或多步骤的注册过程，认为研究主要针对特定疾病的患者，以及对研究如何在AD低风险人群中预防AD的困惑。焦点小组还透露，由于对政府和科学界的不信任程度更高，黑人/非裔美国人参与者在加入登记册时比西班牙裔/拉丁裔人表达了更多的犹豫。结论：招募更多的黑人/非裔美国人和西班牙裔/拉丁裔参与者参与AD研究至关重要。这项混合方法研究表明，这些代表性不足的群体中的成年人有动机预防AD，并愿意使用移动设备注册AD参与者招募登记处。加入注册中心的大多数障碍可以通过对注册中心的设计和功能进行轻微修改并添加内容来解决。这些发现有助于提高加入AD招募登记处的吸引力，最终招募更具多样性和代表性的参与者群体，并提高AD研究结果的可推广性。

{"title":"Understanding Barriers and Facilitators to Signing Up for a Mobile-Responsive Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer's Disease Prevention Studies.","authors":"D Neffa-Creech, R Aggarwal, C Stowell, U Menon, S George, A Plant, J B Langbaum","doi":"10.14283/jpad.2023.67","DOIUrl":"10.14283/jpad.2023.67","url":null,"abstract":"Background: Alzheimer's disease (AD) disproportionately affects Black/African American and Hispanic/Latino adults, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings.Objectives: This study explores barriers and facilitators to signing up for an AD participant recruitment registry website intended to optimize recruitment of these adults. The registry is geared toward recruitment on smartphones and tablets (mobile devices), as research suggests that mobile-first approaches may be more successful within these populations.Design: In 2020, we conducted four focus groups (n = 39) and an online survey (n = 1010) with Black/African American and Hispanic/Latino adults. The survey also included Whites as a comparison group.Setting: Focus groups were in-person at research facilities in New Orleans, Louisiana, and Los Angeles, California. The online survey was distributed by a survey panel company to participants nationwide.Participants: Black/African American (n = 360), Hispanic/Latino (n = 359), or White (n = 330) individuals, 45-75 years old, who self-reported not having mild cognitive impairment (MCI), dementia, or AD.Measurements: Barriers and facilitators explored in the focus groups and survey were related to health and AD (e.g., AD-related concerns and past participation/willingness to participate in health or AD studies); current use of mobile devices (e.g., comfort using devices and receptivity to the AD recruitment registry); and participant characteristics and beliefs (e.g., demographics, health literacy level, and trust in government and the scientific community).Results: The focus groups and survey revealed similar findings. Participants commonly use mobile devices to go online and perform health-related activities. They were aware of AD, expressed concerns with developing it, and were willing to participate in AD-related studies (motivated by personal connection to AD, altruism, and compensation). When presented with the AD recruitment registry, most provided positive feedback (e.g., easy to use and informative) and shared an interest in joining. Barriers to joining the registry with a mobile device included complex or multistep enrollment processes, beliefs that studies are primarily for those with a specific disease, and confusion about how studies can prevent AD among those low-risk for AD. The focus groups also revealed that Black/African American participants expressed more hesitation than Hispanic/Latinos in joining the registry due to greater distrust in the government and scientific community.Conclusions: Recruiting more Black/African American and Hispanic/Latino participants into AD studies is vitally important. This mixed methods study suggests that adults in these underrepres","PeriodicalId":48606,"journal":{"name":"Jpad-Journal of Prevention of Alzheimers Disease","volume":"10 1","pages":"865-874"},"PeriodicalIF":6.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10884139/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66894094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0