Pub Date : 2024-11-01Epub Date: 2024-10-29DOI: 10.1177/13872877241289397
Xinyang Zhang, Renhua Lv, Yanqiu Sun, Timon Cheng-Yi Liu
Background: The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain.
Objective: This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD.
Methods: The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS.
Results: Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: -0.40, 95% CI: -0.43 to -0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI -0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: -0.76 to 1.20).
Conclusions: γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home.
{"title":"The safety and effectiveness of 40 Hz γ-tACS in Alzheimer's disease: A meta-analysis.","authors":"Xinyang Zhang, Renhua Lv, Yanqiu Sun, Timon Cheng-Yi Liu","doi":"10.1177/13872877241289397","DOIUrl":"https://doi.org/10.1177/13872877241289397","url":null,"abstract":"<p><strong>Background: </strong>The efficacy and safety of 40 Hz gamma transcranial alternating current stimulation (γ-tACS) in Alzheimer's disease (AD) are still uncertain.</p><p><strong>Objective: </strong>This meta-analysis was conducted to investigate the therapeutic potential and safety of 40 Hz γ-tACS for AD.</p><p><strong>Methods: </strong>The meta-analysis was conducted by systematically searching four databases from their start to 28 December 2023. Subgroup analyses were performed to identify the intervention effects of γ-tACS.</p><p><strong>Results: </strong>Of the 7 included studies, γ-tACS has a notable impact on improving overall cognition [standardized mean difference (SMD): 0.49, 95% CI: 0.09 to 0.89], memory (SMD: 0.79, 95% CI: 0.18 to 1.41), and cholinergic transmission (weighted mean difference: -0.40, 95% CI: -0.43 to -0.37). Furthermore, subgroup analysis revealed that γ-tACS treatment had a substantial impact on enhancing memory targeting the left angular gyrus in both home (SMD: 3.12, 95% CI: 1.54 to 4.70) and non-home settings (SMD: 0.53, 95% CI: 0.24 to 0.82). However, γ-tACS had a positive effect on overall cognition in non-home settings (SMD: 0.55, 95% CI 0.11 to 0.98), but not in home settings (SMD: 0.22, 95% CI -0.76 to 1.20). Additionally, targeting temporo-frontal or bitemporal γ-tACS treatment resulted in improvement in overall cognition (SMD: 0.61, 95% CI: 0.06 to 1.16), but not targeting the left angular gyrus (SMD: 0.22, 95% CI: -0.76 to 1.20).</p><p><strong>Conclusions: </strong>γ-tACS could be beneficial in enhancing cognition, memory and restoring cholinergic dysfunction in AD. The different selection of stimulation sites plays distinct roles. Meanwhile, AD patients are recommended to receive γ-tACS treatment at home.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 2","pages":"295-307"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687013","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}
Pub Date : 2024-11-01Epub Date: 2024-10-03DOI: 10.1177/13872877241283678
Yicheng Lin, Sheng-Han Kuo
The cerebellum has been largely overlooked in Alzheimer's disease, despite increasing evidence implicating its cognitive capacities and functional networks, which interacts with cerebral cortex to subserve cognition. A study by Lin et al. has indicated that the cerebellum is part of the integrated network in amnestic mild cognitive impairment (aMCI), a prodromal state of Alzheimer's disease. The aMCI patients exhibited weaker cerebello-parietal functional connectivity but stronger cerebellar coupling with precuneus cortex, posterior cingulate gyrus, and caudate nucleus. These alterations in cerebello-cortical connectivity correlated with cognitive performance, suggesting a dynamic change of cerebello-cortical network related to cognitive change in aMCI.
{"title":"The emerging role of the cerebellum in neurodegeneration linked to cognitive impairment.","authors":"Yicheng Lin, Sheng-Han Kuo","doi":"10.1177/13872877241283678","DOIUrl":"https://doi.org/10.1177/13872877241283678","url":null,"abstract":"<p><p>The cerebellum has been largely overlooked in Alzheimer's disease, despite increasing evidence implicating its cognitive capacities and functional networks, which interacts with cerebral cortex to subserve cognition. A study by Lin et al. has indicated that the cerebellum is part of the integrated network in amnestic mild cognitive impairment (aMCI), a prodromal state of Alzheimer's disease. The aMCI patients exhibited weaker cerebello-parietal functional connectivity but stronger cerebellar coupling with precuneus cortex, posterior cingulate gyrus, and caudate nucleus. These alterations in cerebello-cortical connectivity correlated with cognitive performance, suggesting a dynamic change of cerebello-cortical network related to cognitive change in aMCI.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 1","pages":"30-32"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576262","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}
Pub Date : 2024-11-01Epub Date: 2024-11-03DOI: 10.1177/13872877241289053
Hattapark Dejakaisaya, Runxuan Lin, Anna Harutyunyan, Jianxiong Chan, Patrick Kwan, Nigel C Jones
Background: Individuals with Alzheimer's disease (AD) have a heightened risk of epilepsy. However, the underlying mechanisms are not well-understood.
Objective: We aimed to elucidate the role of the glutamate-glutamine cycle in this mechanism and test the effect of ceftriaxone, a glutamate transporter-1 (GLT-1) enhancer, on seizure susceptibility in the Tg2576 mouse model of AD.
Methods: First, we assessed expression levels of key proteins in the glutamate-glutamine cycle in Tg2576 (n = 7) and wild-type littermates (n = 7), and subsequently in the kindling model of epilepsy (n = 6) and sham (n = 6). Then, kindling susceptibility was assessed in three groups: 200 mg/kg ceftriaxone-treated Tg2576 (Tg-Ceft, n = 9); saline-treated Tg2576 (Tg-Sal, n = 9); and saline-treated wild-type (WT-Sal, n = 15). Mice were treated for seven days before kindling, and seizure susceptibility compared between groups.
Results: Protein levels of GLT-1 (p = 0.0093) and glutamine synthetase (p = 0.0016) were reduced in cortex of Tg2576 mice, compared to WT. Kindling increased GLT-1 (cortex: p < 0.0001, hippocampus: p = 0.0075), and glutaminase (cortex: p = 0.0044) protein levels, compared to sham. Both Tg-Ceft and WT-Sal displayed Class IV seizures in response to the first stimulation (p > 0.99), while Tg-Sal displayed Class V seizure (p = 0.0212 versus WT-Sal). Seizure susceptibility of Tg-Ceft was not different from Tg-Sal (p > 0.05), and kindling rates did not differ between groups.
Conclusions: Disruptions to key components of the glutamate-glutamine cycle are observed in models of AD and epilepsy. However, increasing GLT-1 through ceftriaxone treatment did not influence seizure susceptibility in Tg2576 mice, suggesting this is not an effective strategy to lower seizure susceptibility in AD, or a higher dosage is needed.
{"title":"Effect of ceftriaxone on the glutamate-glutamine cycle and seizure susceptibility of Tg2576 mouse model of Alzheimer's disease.","authors":"Hattapark Dejakaisaya, Runxuan Lin, Anna Harutyunyan, Jianxiong Chan, Patrick Kwan, Nigel C Jones","doi":"10.1177/13872877241289053","DOIUrl":"10.1177/13872877241289053","url":null,"abstract":"<p><strong>Background: </strong>Individuals with Alzheimer's disease (AD) have a heightened risk of epilepsy. However, the underlying mechanisms are not well-understood.</p><p><strong>Objective: </strong>We aimed to elucidate the role of the glutamate-glutamine cycle in this mechanism and test the effect of ceftriaxone, a glutamate transporter-1 (GLT-1) enhancer, on seizure susceptibility in the Tg2576 mouse model of AD.</p><p><strong>Methods: </strong>First, we assessed expression levels of key proteins in the glutamate-glutamine cycle in Tg2576 (<i>n</i> = 7) and wild-type littermates (<i>n</i> = 7), and subsequently in the kindling model of epilepsy (<i>n</i> = 6) and sham (<i>n</i> = 6). Then, kindling susceptibility was assessed in three groups: 200 mg/kg ceftriaxone-treated Tg2576 (Tg-Ceft, <i>n</i> = 9); saline-treated Tg2576 (Tg-Sal, <i>n</i> = 9); and saline-treated wild-type (WT-Sal, <i>n</i> = 15). Mice were treated for seven days before kindling, and seizure susceptibility compared between groups.</p><p><strong>Results: </strong>Protein levels of GLT-1 (<i>p</i> = 0.0093) and glutamine synthetase (<i>p</i> = 0.0016) were reduced in cortex of Tg2576 mice, compared to WT. Kindling increased GLT-1 (cortex: <i>p</i> < 0.0001, hippocampus: <i>p</i> = 0.0075), and glutaminase (cortex: <i>p</i> = 0.0044) protein levels, compared to sham. Both Tg-Ceft and WT-Sal displayed Class IV seizures in response to the first stimulation (<i>p</i> > 0.99), while Tg-Sal displayed Class V seizure (<i>p</i> = 0.0212 versus WT-Sal). Seizure susceptibility of Tg-Ceft was not different from Tg-Sal (<i>p</i> > 0.05), and kindling rates did not differ between groups.</p><p><strong>Conclusions: </strong>Disruptions to key components of the glutamate-glutamine cycle are observed in models of AD and epilepsy. However, increasing GLT-1 through ceftriaxone treatment did not influence seizure susceptibility in Tg2576 mice, suggesting this is not an effective strategy to lower seizure susceptibility in AD, or a higher dosage is needed.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"370-381"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576091","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}
Recent studies indicate that gut microbiota may play a crucial role in cognitive function. Individuals with cognitive impairment tend to have fewer beneficial gut bacteria and lower microbial diversity. Therefore, gut microbiota could be a potential biomarker for cognitive vulnerability. Further research is needed to understand the mechanisms and lifestyle factors affecting both microbiota composition and cognitive health. While the direct impact of microbiota and diet on cognitive impairment remains unconfirmed, this area holds promise for developing new preventive and treatment strategies.
{"title":"Microbiota and cognitive impairment: Current challenges and future perspectives.","authors":"Guillaume Chapelet, Wendy Noble, Pascal Derkinderen","doi":"10.1177/13872877241289057","DOIUrl":"10.1177/13872877241289057","url":null,"abstract":"<p><p>Recent studies indicate that gut microbiota may play a crucial role in cognitive function. Individuals with cognitive impairment tend to have fewer beneficial gut bacteria and lower microbial diversity. Therefore, gut microbiota could be a potential biomarker for cognitive vulnerability. Further research is needed to understand the mechanisms and lifestyle factors affecting both microbiota composition and cognitive health. While the direct impact of microbiota and diet on cognitive impairment remains unconfirmed, this area holds promise for developing new preventive and treatment strategies.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"311-313"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576096","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}
Pub Date : 2024-11-01Epub Date: 2024-11-12DOI: 10.1177/13872877241290123
Marissa Ciesla, Claudio Toro-Serey, Ali Jannati, Russell E Banks, Joyce Gomes-Osman, John Showalter, David Bates, Sean Tobyne, Alvaro Pascual-Leone
Background: Distinguishing between mild cognitive impairment (MCI) and early dementia requires both neuropsychological and functional assessment that often relies on caregivers' insights. Contacting a patient's caregiver can be time-consuming in a physician's already-filled workday.
Objective: To assess the utility of a brief, machine learning (ML)-enabled digital cognitive assessment, the Digital Clock and Recall (DCR), for detecting functional dependence.
Methods: We evaluated whether the DCR can help identify individuals at risk of functional deficits as measured by the informant-rated Functional Activities Questionnaire (FAQ) in older individuals including cognitively unimpaired, MCI, and dementia likely due to Alzheimer's disease.
Results: The DCR scaled well with FAQ scores, and ML classifiers trained on multimodal DCR features demonstrated strong performance in predicting functional impairment on a held-out test set. Differences in FAQ scores between DCR-predicted classes were comparable across key demographic groups.
Conclusions: The DCR can streamline the clinical decision-making, triage, and intervention planning associated with functional impairment in primary care.
{"title":"Detecting functional impairment with the Digital Clock and Recall.","authors":"Marissa Ciesla, Claudio Toro-Serey, Ali Jannati, Russell E Banks, Joyce Gomes-Osman, John Showalter, David Bates, Sean Tobyne, Alvaro Pascual-Leone","doi":"10.1177/13872877241290123","DOIUrl":"10.1177/13872877241290123","url":null,"abstract":"<p><strong>Background: </strong>Distinguishing between mild cognitive impairment (MCI) and early dementia requires both neuropsychological and functional assessment that often relies on caregivers' insights. Contacting a patient's caregiver can be time-consuming in a physician's already-filled workday.</p><p><strong>Objective: </strong>To assess the utility of a brief, machine learning (ML)-enabled digital cognitive assessment, the Digital Clock and Recall (DCR), for detecting functional dependence.</p><p><strong>Methods: </strong>We evaluated whether the DCR can help identify individuals at risk of functional deficits as measured by the informant-rated Functional Activities Questionnaire (FAQ) in older individuals including cognitively unimpaired, MCI, and dementia likely due to Alzheimer's disease.</p><p><strong>Results: </strong>The DCR scaled well with FAQ scores, and ML classifiers trained on multimodal DCR features demonstrated strong performance in predicting functional impairment on a held-out test set. Differences in FAQ scores between DCR-predicted classes were comparable across key demographic groups.</p><p><strong>Conclusions: </strong>The DCR can streamline the clinical decision-making, triage, and intervention planning associated with functional impairment in primary care.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"329-337"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620781","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}
Pub Date : 2024-11-01Epub Date: 2024-10-23DOI: 10.3233/JAD-240646
Noelia Calvo, G Peggy McFall, Shreeyaa Ramana, Michelle Galper, Esme Fuller-Thomson, Roger A Dixon, Gillian Einstein
Background: Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM).
Methods: A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), APOE4, body mass index (BMI), cancer history, and smoking history.
Results: Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. APOE4 (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]).
Conclusions: Women with early BO, particularly with an APOE4 allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.
背景:双侧输卵管切除术(BO)会导致雌二醇立即减少。我们研究了早期卵巢切除术妇女中阿尔茨海默病(AD)的发病率和预测因素,并将其与自然绝经妇女(SM)的AD几率进行了比较:方法:英国生物库(UK Biobank)中的一个队列(n = 34,603)包括了基线年龄在 60 岁以上、患有或不患有老年痴呆症的早期更年期妇女或自然更年期妇女。AD是根据与AD相关的ICD-10或ICD-9代码确定的。我们使用逻辑回归法建立了绝经类型与注意力缺失症的关系模型。模型预测因素包括年龄、教育程度、绝经年龄、激素治疗(HT)、APOE4、体重指数(BMI)、癌症史和吸烟史:与 SM 患者相比,早期 BO 患者罹患 AD 的几率是后者的四倍(OR = 4.12,95% CI [2.02,8.44])。APOE4(OR=4.29,95% CI [2.43,7.56])和年龄较大(OR=1.16,95% CI [1.05,1.28])与BO组患AD的几率增加有关。受教育年限越长,BO组(OR = 0.91,95% CI [0.85,0.98])和SM组(OR = 0.95,95% CI [0.90,0.99])的AD几率越低,而曾经使用过HT仅与BO组的AD几率降低有关(OR = 0.43,95% CI [0.23,0.82]):结论:患有早期BO的女性,尤其是具有APOE4等位基因的女性,罹患AD的风险很高。结论:患有早期高血压的女性,尤其是具有 APOE4 等位基因的女性,患有高血压的风险较高。
{"title":"Associated risk and resilience factors of Alzheimer's disease in women with early bilateral oophorectomy: Data from the UK Biobank.","authors":"Noelia Calvo, G Peggy McFall, Shreeyaa Ramana, Michelle Galper, Esme Fuller-Thomson, Roger A Dixon, Gillian Einstein","doi":"10.3233/JAD-240646","DOIUrl":"https://doi.org/10.3233/JAD-240646","url":null,"abstract":"<p><strong>Background: </strong>Bilateral oophorectomy (BO) confers immediate estradiol loss. We examined prevalence and predictors of Alzheimer's disease (AD) in women with early BO comparing their odds ratios of AD to those of women with spontaneous menopause (SM).</p><p><strong>Methods: </strong>A cohort from UK Biobank (n = 34,603) included women aged 60 + at baseline with and without AD who had early BO or SM. AD was determined based on AD related ICD-10 or ICD-9 code. We used logistic regression to model the association of menopause type with AD. Model predictors included age, education, age at menopause, hormone therapy (HT), <i>APOE4</i>, body mass index (BMI), cancer history, and smoking history.</p><p><strong>Results: </strong>Those with early BO had four times the odds of developing AD (OR = 4.12, 95% CI [2.02, 8.44]) compared to those with SM. <i>APOE4</i> (OR = 4.29, 95% CI [2.43, 7.56]), and older age (OR = 1.16, 95% CI [1.05, 1.28]) were associated with increased odds of AD in the BO group. Greater years of education were associated with reduced odds of AD for both BO (OR = 0.91, 95% CI [0.85, 0.98]), and SM (OR = 0.95, 95% CI [0.90, 0.99]), while ever use of HT was associated with decreased odds of AD only for the BO group (OR = 0.43, 95% CI [0.23, 0.82]).</p><p><strong>Conclusions: </strong>Women with early BO, particularly with an <i>APOE4</i> allele, are at high risk of AD. Women with early BO who use HT and those with increased education have lower odds of developing AD.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 1","pages":"119-128"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576143","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}
Pub Date : 2024-11-01Epub Date: 2024-10-17DOI: 10.1177/13872877241284211
Laura Serra, Sabrina Bonarota, Carlotta Di Domenico, Giulia Caruso, Giovanni Giulietti, Martina Rizzuti, Martina Assogna, Marta Rodini, Lucia Mencarelli, Francesco Di Lorenzo, Giacomo Koch, Lucia Fadda, Carlo Caltagirone, Marco Bozzali
Background: Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves.
Objective: This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum.
Methods: 35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses.
Results: Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls.
Conclusions: This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.
{"title":"The funnel effect of reserves prompted by leisure activities across the Alzheimer's disease continuum.","authors":"Laura Serra, Sabrina Bonarota, Carlotta Di Domenico, Giulia Caruso, Giovanni Giulietti, Martina Rizzuti, Martina Assogna, Marta Rodini, Lucia Mencarelli, Francesco Di Lorenzo, Giacomo Koch, Lucia Fadda, Carlo Caltagirone, Marco Bozzali","doi":"10.1177/13872877241284211","DOIUrl":"https://doi.org/10.1177/13872877241284211","url":null,"abstract":"<p><strong>Background: </strong>Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves.</p><p><strong>Objective: </strong>This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum.</p><p><strong>Methods: </strong>35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses.</p><p><strong>Results: </strong>Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls.</p><p><strong>Conclusions: </strong>This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 1","pages":"181-194"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576267","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}
Pub Date : 2024-11-01Epub Date: 2024-11-10DOI: 10.1177/13872877241290127
Zachary T Goodman, Maria M Llabre, Sonya Kaur, Nikhil Banerjee, Katalina McInerney, Xiaoyan Sun, Anita Seixas Dias Saporta, Bonnie E Levin
Background: Mild cognitive impairment (MCI) is a heterogeneous diagnostic entity, without a clear prognosis, often accompanied by psychiatric symptomatology and physical frailty.
Objective: Understanding the heterogeneity within MCI is a critical step in improving the early detection of cognitive decline and developing effective interventions.
Methods: Cross-sectional multivariate latent mixture analyses of data from patients evaluated between 2015 and 2019, who were routinely entered into a multidisciplinary database for research purposes. A sample of 538 community-dwelling older adults drawn from a large academic medical center, referred from within the Department of Neurology (63.7% Female, Mage = 67.8, SDage = 10.6). Participants completed comprehensive neuropsychological assessments, psychiatric symptom measures, and frailty evaluations.
Results: Latent profile analyses supported five profiles of cognitive impairment: At-Risk, Pre-MCI, Amnestic MCI, Multiple Domain MCI, and Major Cognitive Impairment. The inclusion of concomitant psychiatric symptoms and frailty criteria revealed two additional profiles: Psychiatric/Frail, without cognitive impairments, and Multiple Cognitive Domains/Psychiatric/Frail. Critically, 55% of those classified as Healthy based on cognitive data alone were reclassified. Significant profile-wise differences emerged across auxiliary variables of brief cognitive screening, sociodemographics, and medical and psychosocial risk.
Conclusions: Results highlight heterogeneity represented by neurologic patients referred for neuropsychological evaluation that include key physical and emotional symptoms known to increase the risk of cognitive decline. Findings are in alignment with more recent research suggesting that the traditional paradigm cognitive impairment may need to be expanded to improve diagnostic accuracy and to develop more tailored, precision-driven interventions.
{"title":"Exploring heterogeneity in mild cognitive impairment.","authors":"Zachary T Goodman, Maria M Llabre, Sonya Kaur, Nikhil Banerjee, Katalina McInerney, Xiaoyan Sun, Anita Seixas Dias Saporta, Bonnie E Levin","doi":"10.1177/13872877241290127","DOIUrl":"10.1177/13872877241290127","url":null,"abstract":"<p><strong>Background: </strong>Mild cognitive impairment (MCI) is a heterogeneous diagnostic entity, without a clear prognosis, often accompanied by psychiatric symptomatology and physical frailty.</p><p><strong>Objective: </strong>Understanding the heterogeneity within MCI is a critical step in improving the early detection of cognitive decline and developing effective interventions.</p><p><strong>Methods: </strong>Cross-sectional multivariate latent mixture analyses of data from patients evaluated between 2015 and 2019, who were routinely entered into a multidisciplinary database for research purposes. A sample of 538 community-dwelling older adults drawn from a large academic medical center, referred from within the Department of Neurology (63.7% Female, <i>M</i><sub>age </sub>= 67.8, <i>SD</i><sub>age </sub>= 10.6). Participants completed comprehensive neuropsychological assessments, psychiatric symptom measures, and frailty evaluations.</p><p><strong>Results: </strong>Latent profile analyses supported five profiles of cognitive impairment: <i>At-Risk</i>, <i>Pre-MCI</i>, <i>Amnestic MCI</i>, <i>Multiple Domain MCI</i>, and <i>Major Cognitive Impairment</i>. The inclusion of concomitant psychiatric symptoms and frailty criteria revealed two additional profiles: <i>Psychiatric/Frail</i>, without cognitive impairments, and <i>Multiple Cognitive Domains/Psychiatric/Frail</i>. Critically, 55% of those classified as <i>Healthy</i> based on cognitive data alone were reclassified. Significant profile-wise differences emerged across auxiliary variables of brief cognitive screening, sociodemographics, and medical and psychosocial risk.</p><p><strong>Conclusions: </strong>Results highlight heterogeneity represented by neurologic patients referred for neuropsychological evaluation that include key physical and emotional symptoms known to increase the risk of cognitive decline. Findings are in alignment with more recent research suggesting that the traditional paradigm cognitive impairment may need to be expanded to improve diagnostic accuracy and to develop more tailored, precision-driven interventions.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":" ","pages":"411-423"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142620822","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}
Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood.
Objective: We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis.
Methods: We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted.
Results: There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions.
Conclusions: Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.
背景:阿尔茨海默病(AD)的特征是淀粉样蛋白-β和tau蛋白的积累,导致神经纤维缠结。一种基于生物标志物的诊断方法称为 ATN 系统,它将 AD 病理分为淀粉样蛋白-β(A)、tau 蛋白(T)和神经变性(N)。临床前 AD 阶段区域性 tau 沉积与葡萄糖代谢降低之间的关系尚不十分清楚:我们展示了逐个象素的代谢/tau沉积比(MTR)图像,以研究tau沉积对AD大脑代谢的影响:我们选择了174名受试者,他们接受了3D-MRI、FDG-PET、淀粉样蛋白PET和tau PET扫描。通过将 FDG-PET 与 MK6240 PET 图像进行归一化,创建了 MTR 图像。对 63 名认知正常的淀粉样蛋白阴性(CNA)受试者、49 名注意力缺失性痴呆(ADD)受试者、23 名注意力缺失性痴呆所致轻度认知障碍(MCA)受试者和 39 名临床前注意力缺失性痴呆(PRC)受试者进行了象素比较:结果:与CNA相比,ADD和MCA组的葡萄糖代谢减少,主要集中在顶颞区。在ADD组中,Tau沉积的区域更广,而在MCA组中,Tau沉积仅限于颞叶内侧。在ADD和MCA中,MTR在更广泛的区域显示出明显的减少,表明葡萄糖代谢下降和tau沉积同时发生。在MCA和PRC阶段,FDG PET和tau PET分别显示葡萄糖代谢障碍和tau沉积在不同的区域,而MTR图像则显示这两个区域都有障碍:我们的研究结果表明,MTR成像可同时评估糖代谢和tau沉积,有助于深入了解AD的病理生理学。在AD的早期阶段(MCA和PRC),代谢下降和tau沉积在不同的脑区独立发生。
{"title":"Regional differences in glucose metabolic decline and tau deposition in the Alzheimer's continuum brain.","authors":"Kazunari Ishii, Takahiro Yamada, Kohei Hanaoka, Hayato Kaida, Yasuyuki Kojita, Atsushi Kono, Kazushi Hanada, Kazumasa Saigoh, Shizuka Sakuta, Mamoru Hashimoto, Takashi Kato, Akinori Nakamura","doi":"10.1177/13872877241284314","DOIUrl":"https://doi.org/10.1177/13872877241284314","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β and tau proteins, leading to neurofibrillary tangles. A biomarker-based diagnostic method called the ATN system categorizes AD pathology into amyloid-β (A), tau (T), and neurodegeneration (N). The relationship between regional tau deposition and reduced glucose metabolism in the preclinical AD stage is not well understood.</p><p><strong>Objective: </strong>We presented voxel-by-voxel metabolic/tau deposition ratio (MTR) images to investigate the effects of tau deposition on metabolism in AD brains on a stage-by-stage basis.</p><p><strong>Methods: </strong>We selected 174 subjects who underwent 3D-MRI, FDG-PET, amyloid PET, and tau PET scans. MTR images were created by normalizing FDG-PET toMK6240 PET images. Voxel-wise comparisons among 63 cognitively normal amyloid-negative (CNA) subjects, 49 subjects with AD dementia (ADD), 23 subjects with mild cognitive impairment due to AD (MCA), and 39 preclinical AD (PRC) subjects were conducted.</p><p><strong>Results: </strong>There was reduced glucose metabolism in ADD and MCA groups compared to CNA, predominantly in parietotemporal areas. Tau deposition was observed in wider areas in ADD and restricted to the medial temporal lobes in MCA. MTR exhibited significant reductions in broader regions in ADD and MCA, indicating simultaneous glucose metabolism decrease and tau deposition. At the MCA and PRC stages, glucose metabolism impairment and tau deposition were shown in separate regions by FDG PET and tau PET, respectively, while MTR images showed impairment in both regions.</p><p><strong>Conclusions: </strong>Our findings suggest that MTR imaging provides insights into AD pathophysiology by simultaneously assessing glucose metabolism and tau deposition. In the early stage of the AD continuum (MCA and PRC), metabolic decline and tau deposition occur independently in different brain regions.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 1","pages":"228-236"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576237","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}
Background: Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population.
Objective: Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (APOE) ɛ4 status) risk factors in detecting preclinical AD.
Methods: 125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors APOE ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ42/40 ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4.
Results: The best model for predicting Aβ PET status included age, years of education, APOE ɛ4 status, Aβ42/40 ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model.
Conclusions: Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.
背景:最近出现了一些血浆生物标志物,可用于阿尔茨海默病(AD)的诊断、评估和疾病监测,但尚未在临床前AD中得到充分验证。除了阿兹海默病病理血浆生物标志物(淀粉样蛋白-β(Aβ)和磷酸化 tau(p-tau)物种)外,蛋白质组面板还能区分有症状的阿兹海默病和痴呆症门诊人群中认知功能未受损的老年人:方法:使用多元回归法分析了 125 名完成了 Aβ PET 和血浆抽样的认知功能未受损的老年人(平均年龄 = 66 岁),以 Aβ PET 状态(阳性与阴性)为结果,确定预测临床前 AD 的最佳拟合值。模型 1 包括年龄、教育程度和性别。模型 2 和 3 分别增加了 APOE ɛ4 状态(携带者与非携带者)和 AD 病理血液生物标记物(Aβ42/40 比率、p-tau181)预测因子。随机森林模型确定了蛋白质组中最能预测 Aβ PET 状态的 5 个蛋白质组标记物,并将这些标记物添加到模型 4.结果中:结果:预测 Aβ PET 状态的最佳模型包括年龄、受教育年限、APOE ɛ4 状态、Aβ42/40 比率和 p-tau181。加入前 5 个蛋白质组标记物并不能明显改善模型:在该样本中,血浆中的蛋白质组标记物在预测临床前注意力缺失症方面没有增加标准注意力缺失症病理血浆生物标记物的预测价值。
{"title":"Added value of inflammatory plasma biomarkers to pathologic biomarkers in predicting preclinical Alzheimer's disease.","authors":"Haley Leclerc, Athene Kw Lee, Zachary J Kunicki, Jessica Alber","doi":"10.1177/13872877241283692","DOIUrl":"10.1177/13872877241283692","url":null,"abstract":"<p><strong>Background: </strong>Plasma biomarkers have recently emerged for the diagnosis, assessment, and disease monitoring of Alzheimer's disease (AD), but have yet to be fully validated in preclinical AD. In addition to AD pathologic plasma biomarkers (amyloid-β (Aβ) and phosphorylated tau (p-tau) species), a proteomic panel can discriminate between symptomatic AD and cognitively unimpaired older adults in a dementia clinic population.</p><p><strong>Objective: </strong>Examine the added value of a plasma proteomic panel, validated in symptomatic AD, over standard AD pathologic plasma biomarkers and demographic and genetic (apolipoprotein (<i>APOE</i>) ɛ4 status) risk factors in detecting preclinical AD.</p><p><strong>Methods: </strong>125 cognitively unimpaired older adults (mean age = 66 years) who completed Aβ PET and plasma draw were analyzed using multiple regression with Aβ PET status (positive versus negative) as the outcome to determine the best fit for predicting preclinical AD. Model 1 included age, education, and gender. Model 2 and 3 added predictors <i>APOE</i> ɛ4 status (carrier versus non-carrier) and AD pathologic blood biomarkers (Aβ<sub>42/40</sub> ratio, p-tau181), respectively. Random forest modeling established the 5 proteomic markers from the proteomic panel that best predicted Aβ PET status, and these markers were added in Model 4.</p><p><strong>Results: </strong>The best model for predicting Aβ PET status included age, years of education, <i>APOE</i> ɛ4 status, Aβ<sub>42/40</sub> ratio, and p-tau181. Adding the top 5 proteomic markers did not significantly improve the model.</p><p><strong>Conclusions: </strong>Proteomic markers in plasma did not add predictive value to standard AD pathologic plasma biomarkers in predicting preclinical AD in this sample.</p>","PeriodicalId":14929,"journal":{"name":"Journal of Alzheimer's Disease","volume":"102 1","pages":"89-98"},"PeriodicalIF":3.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11540337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142576124","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}