BackgroundEmerging evidence strongly suggests that terminally differentiated neurons in the brain have the potential to undergo a cell cycle‐like process during neuronal aging and in the presence of certain diseases. However, due to their infrequent occurrence and unpredictable distribution within the brain, the molecular characteristics and specific variations associated with these cells in different diseases are still not well understood.MethodBy taking advantage of the wealth of human brain single‐nucleus RNA sequencing (snRNA‐seq) datasets available in public repositories, we developed an analytical pipeline that facilitates the identification and characterization of cell cycle gene re‐expressing neurons to address these questions. The cell cycle gene expression status of each single nucleus was identified and subsequently tested for DNA duplication or deletion events might be due to aberrant cell cycle activity. Subsequently, the target cells of interest were further characterized via cell fate trajectory analysis to uncover their origins and evolutionary relationships. Lastly, to understand the potential involvement of these cells in disease development and heterogeneity, we quantitatively analyzed their relative numbers and performed differential gene expression analysis comparing nuclei from control and disease‐affected samples.ResultOur analysis showed that cell cycle‐related events primarily occur in excitatory neurons, with cellular senescence being their likely end fate. The number of neurons re‐engaging in the cell cycle and undergoing senescence decreased during normal brain aging, but in late‐onset Alzheimer’s disease (LOAD), these cells accumulated instead. Transcriptomic profiling of these cells revealed that disease‐specific differences were predominantly associated with early‐stage senescence, indicating increased proinflammatory, metabolic dysregulation, and pathology‐related signatures in diseased brains. Similar features were observed in a subset of dopaminergic neurons in the Parkinson’s disease (PD)‐Lewy body dementia (LBD) model and a mouse model of aging.ConclusionThe consistent findings in multiple disease models validated the robust relationship between the cell cycle and senescence events in neurons. The multi‐model analysis conducted in multiple independent datasets demonstrated the applicability and effectiveness of our bioinformatics approach in a cross‐species setting.
{"title":"Cell cycle re‐entry primes neuronal senescence in brain aging and dementia","authors":"Hei‐Man Chow","doi":"10.1002/alz.095808","DOIUrl":"https://doi.org/10.1002/alz.095808","url":null,"abstract":"BackgroundEmerging evidence strongly suggests that terminally differentiated neurons in the brain have the potential to undergo a cell cycle‐like process during neuronal aging and in the presence of certain diseases. However, due to their infrequent occurrence and unpredictable distribution within the brain, the molecular characteristics and specific variations associated with these cells in different diseases are still not well understood.MethodBy taking advantage of the wealth of human brain single‐nucleus RNA sequencing (snRNA‐seq) datasets available in public repositories, we developed an analytical pipeline that facilitates the identification and characterization of cell cycle gene re‐expressing neurons to address these questions. The cell cycle gene expression status of each single nucleus was identified and subsequently tested for DNA duplication or deletion events might be due to aberrant cell cycle activity. Subsequently, the target cells of interest were further characterized via cell fate trajectory analysis to uncover their origins and evolutionary relationships. Lastly, to understand the potential involvement of these cells in disease development and heterogeneity, we quantitatively analyzed their relative numbers and performed differential gene expression analysis comparing nuclei from control and disease‐affected samples.ResultOur analysis showed that cell cycle‐related events primarily occur in excitatory neurons, with cellular senescence being their likely end fate. The number of neurons re‐engaging in the cell cycle and undergoing senescence decreased during normal brain aging, but in late‐onset Alzheimer’s disease (LOAD), these cells accumulated instead. Transcriptomic profiling of these cells revealed that disease‐specific differences were predominantly associated with early‐stage senescence, indicating increased proinflammatory, metabolic dysregulation, and pathology‐related signatures in diseased brains. Similar features were observed in a subset of dopaminergic neurons in the Parkinson’s disease (PD)‐Lewy body dementia (LBD) model and a mouse model of aging.ConclusionThe consistent findings in multiple disease models validated the robust relationship between the cell cycle and senescence events in neurons. The multi‐model analysis conducted in multiple independent datasets demonstrated the applicability and effectiveness of our bioinformatics approach in a cross‐species setting.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"101 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundIn 2023, the World Health Organization (WHO) presented the Mental Health Gap Action Programmes to avert Dementia. In this publication, the WHO presented a high certainty that physical activity interventions prevent Dementia. The organization presented low levels of certainty that psychosocial interventions, non‐pharmaceutical interventions, depression, and anxiety treatments are effective for Dementia prevention in low‐income and middle‐income countries (LMICs). This policy paper utilizes Global evidence, Continental perspective, Regional insight, and County outlook and presents the potential global policies that can avert Dementia, which were omitted in the 2023 WHO report.MethodThis review uses World Bank, World Health Organization, and United Nations datasets. We also comprehensively searched the medical literature for published articles on social and commercial determinants of Dementia.ResultWe demonstrate that the current WHO report does not comprehensively present policies that may yield positive returns in averting Dementia for developing countries. Physical activity is high in LMICs and may do little to prevent Dementia. Countries need to reduce poverty, hunger, tobacco consumption, alcohol consumption, sugar consumption, and other substances as crucial risk factors that drive Dementia outcomes in LMICs. Other policies that may improve Dementia epidemiology are welfare programs presented in Figure 1. These policies have robust chance of averting sixty percent of the Dementia cases.ConclusionThere is a significant risk of failing to improve Dementia outcomes if the current 2023 WHO report is not amended. Policymakers must address both the social and commercial determinants factors of Dementia as countries seek to achieve healthy brain aging.
{"title":"Economics of Dementia Prevention: Why the 2023 World Health Global Guidelines on Dementia May Not Reduce the Dementia Epidemiology in Developing Countries","authors":"Cyprian M Mostert","doi":"10.1002/alz.094651","DOIUrl":"https://doi.org/10.1002/alz.094651","url":null,"abstract":"BackgroundIn 2023, the World Health Organization (WHO) presented the Mental Health Gap Action Programmes to avert Dementia. In this publication, the WHO presented a high certainty that physical activity interventions prevent Dementia. The organization presented low levels of certainty that psychosocial interventions, non‐pharmaceutical interventions, depression, and anxiety treatments are effective for Dementia prevention in low‐income and middle‐income countries (LMICs). This policy paper utilizes Global evidence, Continental perspective, Regional insight, and County outlook and presents the potential global policies that can avert Dementia, which were omitted in the 2023 WHO report.MethodThis review uses World Bank, World Health Organization, and United Nations datasets. We also comprehensively searched the medical literature for published articles on social and commercial determinants of Dementia.ResultWe demonstrate that the current WHO report does not comprehensively present policies that may yield positive returns in averting Dementia for developing countries. Physical activity is high in LMICs and may do little to prevent Dementia. Countries need to reduce poverty, hunger, tobacco consumption, alcohol consumption, sugar consumption, and other substances as crucial risk factors that drive Dementia outcomes in LMICs. Other policies that may improve Dementia epidemiology are welfare programs presented in Figure 1. These policies have robust chance of averting sixty percent of the Dementia cases.ConclusionThere is a significant risk of failing to improve Dementia outcomes if the current 2023 WHO report is not amended. Policymakers must address both the social and commercial determinants factors of Dementia as countries seek to achieve healthy brain aging.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"35 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Harpreet Kaur, Bretton Badenoch, Peter C. Reifsnyder, Kristen MS O'Connell, Richard A. Miller, David E. Harrison, Catherine C. Kaczorowski
BackgroundPrevious studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.MethodBoth male and female UM‐HET3 mice at age of 11 months (middle‐aged) and 25 months (old) were used in this study. Complete blood count, grip‐strength, Rotarod, visual acuity, startle response, voluntary wheel running activity and contextual fear conditioning assays were performed on these mice. Further, a correlation analysis was performed on blood cells and contextual fear memory (CFM) to identify signatures associated with age related cognitive decline.ResultOur results showed significantly lower body temperature, decrease in hemoglobin, changes in blood related parameters (including RBC, hematocrit, platelets, MPV, WBC), reduced visual acuity, reduced grip strength (not normalized by BW) and impaired memory functions in older mice when compared to middle‐aged mice. We found no correlation between blood cells and CFM in middle‐aged mice, but the percentage of neutrophils (R = 0.794, p = 0.009) and lymphocytes (R = ‐0.734, p = 0.022) were found to be associated with CFM in older male mice. A reduced startle reactivity was also observed in older male and female mice which is likely to be the result of impaired hearing, although these mice were not tested for hearing loss. No statistical significance was observed in Rotarod performance and in wheel running activity when middle aged mice compared to old UM‐HET3 mice.ConclusionOur study showed that UM‐HET3 mice exhibit age related impairment in sensory and memory functions as compared to middle aged mice. In older mice, reduced memory correlates with increased percentage of neutrophils and decreased lymphocytes in blood, suggesting a possible role of white blood cells in age‐related memory decline in UM‐HET3 mice. However, further studies are needed to understand the mechanisms driving age‐related decline in cognition with focus on changes in immune cells for developing therapies to slow down the rate of cognitive decline in normal aging as well as neurological disorders such as Alzheimer’s disease.
{"title":"Age associated changes in behavioral and memory functions in genetically heterogeneous mice UM‐HET3","authors":"Harpreet Kaur, Bretton Badenoch, Peter C. Reifsnyder, Kristen MS O'Connell, Richard A. Miller, David E. Harrison, Catherine C. Kaczorowski","doi":"10.1002/alz.095615","DOIUrl":"https://doi.org/10.1002/alz.095615","url":null,"abstract":"BackgroundPrevious studies have documented age‐related changes in behavior and cognitive functions and investigated the molecular changes in aging brain using inbred mouse strains such as C57BL/6, BALB/c etc. In this study using a genetically heterogenous mouse population (UM‐HET3) we investigated age‐related changes in motor and memory functions and their association with blood cell measures.MethodBoth male and female UM‐HET3 mice at age of 11 months (middle‐aged) and 25 months (old) were used in this study. Complete blood count, grip‐strength, Rotarod, visual acuity, startle response, voluntary wheel running activity and contextual fear conditioning assays were performed on these mice. Further, a correlation analysis was performed on blood cells and contextual fear memory (CFM) to identify signatures associated with age related cognitive decline.ResultOur results showed significantly lower body temperature, decrease in hemoglobin, changes in blood related parameters (including RBC, hematocrit, platelets, MPV, WBC), reduced visual acuity, reduced grip strength (not normalized by BW) and impaired memory functions in older mice when compared to middle‐aged mice. We found no correlation between blood cells and CFM in middle‐aged mice, but the percentage of neutrophils (R = 0.794, p = 0.009) and lymphocytes (R = ‐0.734, p = 0.022) were found to be associated with CFM in older male mice. A reduced startle reactivity was also observed in older male and female mice which is likely to be the result of impaired hearing, although these mice were not tested for hearing loss. No statistical significance was observed in Rotarod performance and in wheel running activity when middle aged mice compared to old UM‐HET3 mice.ConclusionOur study showed that UM‐HET3 mice exhibit age related impairment in sensory and memory functions as compared to middle aged mice. In older mice, reduced memory correlates with increased percentage of neutrophils and decreased lymphocytes in blood, suggesting a possible role of white blood cells in age‐related memory decline in UM‐HET3 mice. However, further studies are needed to understand the mechanisms driving age‐related decline in cognition with focus on changes in immune cells for developing therapies to slow down the rate of cognitive decline in normal aging as well as neurological disorders such as Alzheimer’s disease.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"37 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Claire V Burley, Anna Williams, Genevieve Maiden, Patricia Reyes, Jacquelene Cook, Henry Brodaty, Lynnette Chenoweth
BackgroundOne in four persons living with dementia are admitted to hospital, presenting challenges to them, their carers and staff. Despite global evidence demonstrating the clinical and cost‐effectiveness of person‐centered care (PCC), it is not yet business as usual across healthcare settings. We used multi‐level stakeholder input to implement Kitwood’s PCC model into a sub‐acute setting.MethodsBetween June 2021 to June 2023, the PCC model was implemented and evaluated using the Consolidated Framework for Implementation Research (CFIR) and quantitative and qualitative methods to address the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE‐AIM) framework. Key stakeholders and a strong governance structure including persons living with dementia, family caregivers, clinicians, nurses, hospital leaders, community partners, government officials and policy makers, informed all aspects of implementation and evaluation. Co‐primary outcome measures were delirium and agitation. Data were collected pre‐, post‐ and 6‐months following PCC education.ResultsReach: Ninety nursing, medical and allied health staff (93% of hospital staff) completed online and/or in‐person PCC education; eight senior staff leaders completed in‐person PCC education and took on the role of ‘PCC Champion’ to support staff in implementing PCC. Effectiveness: Significant improvements (all p<.05) were observed in outcomes for persons living with dementia: delirium (phi = 0.73), incidents/injuries (phi = 0.99), psychotropic medication use (phi = 0.09), and readmissions (phi = 0.25). No change was observed for agitation. Adoption: Staff knowledge of and confidence in delivering PCC significantly improved (both p<.005). A significantly higher number of positive (person‐centered) interactions was observed following education (p = 0.000, phi = 0.60), though there was also a high number of neutral interactions. Implementation: PCC education delivery could and was efficiently adapted as required to unplanned crises (i.e. COVID‐19 pandemic). Maintenance: Six‐month follow‐up data showed staff maintained improved PCC knowledge and confidence (both p<.005). However, only three of the eight PCC Champions remained. Suggested modifications to aspects of the model include adopting reflective feedback processes with staff, PCC education for non‐clinical staff, reducing online content to fewer modules, and adapting the education to suit specific cultural groups.ConclusionsThe successful translation of a PCC education model into a sub‐acute rehabilitation setting during a global pandemic has implications for policy and practice.
{"title":"Evaluation of a person‐centred care model for persons living with dementia in the hospital rehabilitation setting using the RE‐AIM framework","authors":"Claire V Burley, Anna Williams, Genevieve Maiden, Patricia Reyes, Jacquelene Cook, Henry Brodaty, Lynnette Chenoweth","doi":"10.1002/alz.092089","DOIUrl":"https://doi.org/10.1002/alz.092089","url":null,"abstract":"BackgroundOne in four persons living with dementia are admitted to hospital, presenting challenges to them, their carers and staff. Despite global evidence demonstrating the clinical and cost‐effectiveness of person‐centered care (PCC), it is not yet <jats:italic>business as usual</jats:italic> across healthcare settings. We used multi‐level stakeholder input to implement Kitwood’s PCC model into a sub‐acute setting.MethodsBetween June 2021 to June 2023, the PCC model was implemented and evaluated using the Consolidated Framework for Implementation Research (CFIR) and quantitative and qualitative methods to address the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE‐AIM) framework. Key stakeholders and a strong governance structure including persons living with dementia, family caregivers, clinicians, nurses, hospital leaders, community partners, government officials and policy makers, informed all aspects of implementation and evaluation. Co‐primary outcome measures were delirium and agitation. Data were collected pre‐, post‐ and 6‐months following PCC education.Results<jats:styled-content>Reach</jats:styled-content>: Ninety nursing, medical and allied health staff (93% of hospital staff) completed online and/or in‐person PCC education; eight senior staff leaders completed in‐person PCC education and took on the role of ‘PCC Champion’ to support staff in implementing PCC. <jats:styled-content>Effectiveness</jats:styled-content>: Significant improvements (all <jats:italic>p</jats:italic><.05) were observed in outcomes for persons living with dementia: delirium (phi = 0.73), incidents/injuries (phi = 0.99), psychotropic medication use (phi = 0.09), and readmissions (phi = 0.25). No change was observed for agitation. <jats:styled-content>Adoption</jats:styled-content>: Staff knowledge of and confidence in delivering PCC significantly improved (both <jats:italic>p</jats:italic><.005). A significantly higher number of positive (person‐centered) interactions was observed following education (p = 0.000, phi = 0.60), though there was also a high number of neutral interactions. <jats:styled-content>Implementation</jats:styled-content>: PCC education delivery could and was efficiently adapted as required to unplanned crises (i.e. COVID‐19 pandemic). <jats:styled-content>Maintenance</jats:styled-content>: Six‐month follow‐up data showed staff maintained improved PCC knowledge and confidence (both <jats:italic>p</jats:italic><.005). However, only three of the eight PCC Champions remained. Suggested modifications to aspects of the model include adopting reflective feedback processes with staff, PCC education for non‐clinical staff, reducing online content to fewer modules, and adapting the education to suit specific cultural groups.ConclusionsThe successful translation of a PCC education model into a sub‐acute rehabilitation setting during a global pandemic has implications for policy and practice.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"35 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936768","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Savvina Chrysostomou, Antonia Tziannarou, Andrea Hadjiloizou, Sotiria Moza
Background A 92‐year‐old retired seamstress, born in 1932, with 12 years of education, had been residing in a long‐term care facility since 2019, following a fall and hip fracture. Post‐admission, her cognitive function gradually declined and she did not participate in residential home activities. This study explores the outcomes of an 8‐month, multisensory remediation program. Methods The individual participated in bi‐weekly, multisensory, group therapy sessions spanning eight months from April to December 2023. The stimuli comprised a blend of visual, tactile, and auditory elements, such as constructive wooden puzzles, knitting wool, sensory balls, kinetic sand, exposure to fabric and clothing, classical music songs, language engagement through discussions, and reminiscence activities. Results Over the course of 8 months, the individual demonstrated qualitative improvements, including active participation in dialogues with neuropsychologists, expressing preferences for stimuli, and displaying increased engagement and willingness to attend sessions. Clinic personnel also noted positive changes in mood, cooperation, interest in interactive activities within the clinic, and enhanced language abilities. These improvements led to the patient relocating to a more team‐oriented table in the common area. As a result of these observed positive changes in the clinical profile, the Mini Mental State Examination (MMSE) was administered in December 2023, yielding a score of 6 out of 30 (points achieved in, naming, reading, orientation and following instructions). Discussion Multisensory therapy may show promise in regard to language and communication skills in elderly individuals with advanced dementia. These positive outcomes may contribute to the patients’ overall well‐being and serve as valuable indicators for treatment evaluation. The study is ongoing to explore long‐term effects and broader implications.
{"title":"Multisensory stimulation in advanced dementia: Insights from a case study","authors":"Savvina Chrysostomou, Antonia Tziannarou, Andrea Hadjiloizou, Sotiria Moza","doi":"10.1002/alz.090742","DOIUrl":"https://doi.org/10.1002/alz.090742","url":null,"abstract":"Background A 92‐year‐old retired seamstress, born in 1932, with 12 years of education, had been residing in a long‐term care facility since 2019, following a fall and hip fracture. Post‐admission, her cognitive function gradually declined and she did not participate in residential home activities. This study explores the outcomes of an 8‐month, multisensory remediation program. Methods The individual participated in bi‐weekly, multisensory, group therapy sessions spanning eight months from April to December 2023. The stimuli comprised a blend of visual, tactile, and auditory elements, such as constructive wooden puzzles, knitting wool, sensory balls, kinetic sand, exposure to fabric and clothing, classical music songs, language engagement through discussions, and reminiscence activities. Results Over the course of 8 months, the individual demonstrated qualitative improvements, including active participation in dialogues with neuropsychologists, expressing preferences for stimuli, and displaying increased engagement and willingness to attend sessions. Clinic personnel also noted positive changes in mood, cooperation, interest in interactive activities within the clinic, and enhanced language abilities. These improvements led to the patient relocating to a more team‐oriented table in the common area. As a result of these observed positive changes in the clinical profile, the Mini Mental State Examination (MMSE) was administered in December 2023, yielding a score of 6 out of 30 (points achieved in, naming, reading, orientation and following instructions). Discussion Multisensory therapy may show promise in regard to language and communication skills in elderly individuals with advanced dementia. These positive outcomes may contribute to the patients’ overall well‐being and serve as valuable indicators for treatment evaluation. The study is ongoing to explore long‐term effects and broader implications.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"37 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tatiana A. Giovannucci, Claire A. Leckey, John Coulton, Henrik Zetterberg, Donald L. Elbert, Randall J. Bateman, Kevin Mills, Selina Wray, Nupur Ghoshal, Chihiro Sato, Ross W. Paterson
BackgroundNeurofilament light protein (NfL) is a promising biomarker of neuronal injury and neurodegeneration. NfL levels in cerebrospinal fluid (CSF) and blood provide information about disease progression and are increasingly relied on as outcome measure in clinical trials. Understanding NfL kinetics in vivo is critical for interpreting NfL in response to new events where a steady state cannot be assumed, such as acute injury, disease onset or progression, or response to disease‐modifying therapies.MethodWe infused human participants with diagnosed primary tauopathies (progressive supranuclear palsy, n = 5; corticobasal syndrome, n = 3; behavioural variant frontotemporal dementia, n = 2) with a stable isotope tracer (13C6‐leucine) and collected CSF by lumbar puncture at 4, 14, 20, 60 and 120 days post‐labelling. In addition, post‐mortem brain tissue from three participants who were infused with the tracer 18, 44 and 50 months earlier were homogenised and biochemically fractionated to separate the soluble and insoluble fraction. NfL was enriched in all samples via immunoprecipitation. The ratio of labelled to unlabelled NfL was measured monitoring proteotypic peptides using established targeted mass spectrometry workflows to quantitate the tracer‐to‐tracee ratio (TTR).ResultAnalysis of CSF detected low labelling of NfL (0.04 – 0.36% TTR) by 120 days that was comparable to the TTR levels detected in the soluble brain fraction. There was NfL present in the insoluble fraction (2.87% of the total NfL at 18‐, 8.87% at 44‐ and 14.03% at 50‐months post‐mortem, averaged across several NfL peptides), with different relative abundances of NfL domains between these fractions. Interestingly, the 13C6‐labelled NfL signal detected in the insoluble fraction was more abundant, despite a higher recovery of total NfL in the soluble fraction.ConclusionNfL turnover in vivo is remarkably slow as it is scarcely captured by 120 days post‐labelling. The labelling results from brain tissue suggest that in these cases of primary tauopathies newly‐synthesized NfL might be delocalized to a pool of protein of low solubility that does not contribute to NfL levels in CSF. Current experiments are addressing whether newly‐synthesized NfL might be sequestered into pathological inclusions.
{"title":"Stable Isotope Labelling Kinetics (SILK) tracing of neurofilament light in human cerebrospinal fluid and brain tissue","authors":"Tatiana A. Giovannucci, Claire A. Leckey, John Coulton, Henrik Zetterberg, Donald L. Elbert, Randall J. Bateman, Kevin Mills, Selina Wray, Nupur Ghoshal, Chihiro Sato, Ross W. Paterson","doi":"10.1002/alz.095735","DOIUrl":"https://doi.org/10.1002/alz.095735","url":null,"abstract":"BackgroundNeurofilament light protein (NfL) is a promising biomarker of neuronal injury and neurodegeneration. NfL levels in cerebrospinal fluid (CSF) and blood provide information about disease progression and are increasingly relied on as outcome measure in clinical trials. Understanding NfL kinetics <jats:italic>in vivo</jats:italic> is critical for interpreting NfL in response to new events where a steady state cannot be assumed, such as acute injury, disease onset or progression, or response to disease‐modifying therapies.MethodWe infused human participants with diagnosed primary tauopathies (progressive supranuclear palsy, n = 5; corticobasal syndrome, n = 3; behavioural variant frontotemporal dementia, n = 2) with a stable isotope tracer (<jats:sup>13</jats:sup>C<jats:sub>6</jats:sub>‐leucine) and collected CSF by lumbar puncture at 4, 14, 20, 60 and 120 days post‐labelling. In addition, <jats:italic>post‐mortem</jats:italic> brain tissue from three participants who were infused with the tracer 18, 44 and 50 months earlier were homogenised and biochemically fractionated to separate the soluble and insoluble fraction. NfL was enriched in all samples via immunoprecipitation. The ratio of labelled to unlabelled NfL was measured monitoring proteotypic peptides using established targeted mass spectrometry workflows to quantitate the tracer‐to‐tracee ratio (TTR).ResultAnalysis of CSF detected low labelling of NfL (0.04 – 0.36% TTR) by 120 days that was comparable to the TTR levels detected in the soluble brain fraction. There was NfL present in the insoluble fraction (2.87% of the total NfL at 18‐, 8.87% at 44‐ and 14.03% at 50‐months <jats:italic>post‐mortem</jats:italic>, averaged across several NfL peptides), with different relative abundances of NfL domains between these fractions. Interestingly, the <jats:sup>13</jats:sup>C<jats:sub>6</jats:sub>‐labelled NfL signal detected in the insoluble fraction was more abundant, despite a higher recovery of total NfL in the soluble fraction.ConclusionNfL turnover <jats:italic>in vivo</jats:italic> is remarkably slow as it is scarcely captured by 120 days post‐labelling. The labelling results from brain tissue suggest that in these cases of primary tauopathies newly‐synthesized NfL might be delocalized to a pool of protein of low solubility that does not contribute to NfL levels in CSF. Current experiments are addressing whether newly‐synthesized NfL might be sequestered into pathological inclusions.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"23 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jetske van der Schaar, Sven J van der Lee, Eva Asscher, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Annelien L. Bredenoord, Mariette A. van den Hoven, Ellen M.A. Smets, Leonie N.C. Visser
BackgroundData‐driven criteria for DNA testing were implemented in routine care of Alzheimer Center Amsterdam. We aimed to explore patients’ perspectives and considerations regarding their decision to (not) be tested for a monogenic cause of their disease.MethodsIn this mixed method study, 150 of 519 new patients visiting Alzheimer Center Amsterdam who fulfilled the criteria were offered DNA‐diagnostics: 86(57%) accepted, 64(43%) did not. In 65/86(76%) cases results were negative, in 14/86(16%) a monogenic cause and in 7/86 (8%) variants of uncertain significance were found (Figure 1). Sex, age, education, family history of dementia, MMSE and diagnosis were retrieved. Before discussing DNA testing, patients completed a questionnaire assessing perceived risk of a genetic cause, susceptibility for, severity of, and experience with dementia, social support, coping strategies, anxiety, depression, and quality of life. Differences between those who did and did not consent to DNA testing were calculated using Pearson’s χ², Mann‐Whitney U or Independent Samples t‐tests; p‐values were FDR‐adjusted. A subset of 22 patients and/or relatives participated in semi‐structured interviews on motivations and considerations regarding their decision. Verbatim transcripts were analyzed inductively using MAXQDA‐software.ResultsParticipants (n = 150) were 46% female and aged 61±8 (MMSE = 22±6, 5 Subjective Cognitive Decline, 9 MCI, 104 dementia [69 AD, 13 FTD, 22 other], 32 other/undetermined). Adjusted for multiple testing, no demographic, medical or psychosocial factors were associated with the decision on DNA testing (all p>0.05). Twenty‐one interviewees who agreed to DNA testing were generally motivated by obtaining information on heredity for their relatives, contributing to scientific research into a treatment, and gaining insight in the cause of their disease. One patient had blood stored, allowing their children to test it when opportune. The majority decided quickly, mostly on intuitions (e.g., responsibility towards relatives) rather than facts (e.g., information on risk and consequences). They expected to feel reassured or relieved by negative test results, and sad or worried if a genetic cause was found.ConclusionsOver half of memory clinic patients eligible for DNA‐testing wanted to be tested. This decision was unrelated to demographic, medical or psychosocial characteristics, and mostly based on intuition and considerations regarding family.
{"title":"Patients’ perceptions and considerations regarding DNA testing in a memory clinic: DNA‐ABOARD","authors":"Jetske van der Schaar, Sven J van der Lee, Eva Asscher, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Annelien L. Bredenoord, Mariette A. van den Hoven, Ellen M.A. Smets, Leonie N.C. Visser","doi":"10.1002/alz.091187","DOIUrl":"https://doi.org/10.1002/alz.091187","url":null,"abstract":"BackgroundData‐driven criteria for DNA testing were implemented in routine care of Alzheimer Center Amsterdam. We aimed to explore patients’ perspectives and considerations regarding their decision to (not) be tested for a monogenic cause of their disease.MethodsIn this mixed method study, 150 of 519 new patients visiting Alzheimer Center Amsterdam who fulfilled the criteria were offered DNA‐diagnostics: 86(57%) accepted, 64(43%) did not. In 65/86(76%) cases results were negative, in 14/86(16%) a monogenic cause and in 7/86 (8%) variants of uncertain significance were found (<jats:italic>Figure 1)</jats:italic>. Sex, age, education, family history of dementia, MMSE and diagnosis were retrieved. Before discussing DNA testing, patients completed a questionnaire assessing perceived risk of a genetic cause, susceptibility for, severity of, and experience with dementia, social support, coping strategies, anxiety, depression, and quality of life. Differences between those who did and did not consent to DNA testing were calculated using Pearson’s χ², Mann‐Whitney U or Independent Samples t‐tests; p‐values were FDR‐adjusted. A subset of 22 patients and/or relatives participated in semi‐structured interviews on motivations and considerations regarding their decision. Verbatim transcripts were analyzed inductively using MAXQDA‐software.ResultsParticipants (n = 150) were 46% female and aged 61±8 (MMSE = 22±6, 5 Subjective Cognitive Decline, 9 MCI, 104 dementia [69 AD, 13 FTD, 22 other], 32 other/undetermined). Adjusted for multiple testing, no demographic, medical or psychosocial factors were associated with the decision on DNA testing (all <jats:italic>p</jats:italic>>0.05). Twenty‐one interviewees who agreed to DNA testing were generally motivated by obtaining information on heredity for their relatives, contributing to scientific research into a treatment, and gaining insight in the cause of their disease. One patient had blood stored, allowing their children to test it when opportune. The majority decided quickly, mostly on intuitions (e.g., responsibility towards relatives) rather than facts (e.g., information on risk and consequences). They expected to feel reassured or relieved by negative test results, and sad or worried if a genetic cause was found.ConclusionsOver half of memory clinic patients eligible for DNA‐testing wanted to be tested. This decision was unrelated to demographic, medical or psychosocial characteristics, and mostly based on intuition and considerations regarding family.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"56 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Support for the management of cognitive and autonomic features of Lewy body dementia (LBD) is offered in detail in this presentation. The US Based Diamond Lewy Cognitive Symptoms management document presents the unique cognitive profile of LBD with general principles for addressing these features along with detailed guidance in the use of cholinesterase inhibitors and Memantine. The US Based Diamond Lewy Autonomic Symptoms management document addresses the management of common autonomic symptoms including urinary dysfunction, male sexual dysfunction, excessive sweating, constipation, sialorrhea, gastroparesis and orthostatic hypotension in LBD.
{"title":"Management of Cognitive and Autonomic Symptoms in LBD","authors":"Douglas W. Scharre","doi":"10.1002/alz.090527","DOIUrl":"https://doi.org/10.1002/alz.090527","url":null,"abstract":"Support for the management of cognitive and autonomic features of Lewy body dementia (LBD) is offered in detail in this presentation. The US Based Diamond Lewy Cognitive Symptoms management document presents the unique cognitive profile of LBD with general principles for addressing these features along with detailed guidance in the use of cholinesterase inhibitors and Memantine. The US Based Diamond Lewy Autonomic Symptoms management document addresses the management of common autonomic symptoms including urinary dysfunction, male sexual dysfunction, excessive sweating, constipation, sialorrhea, gastroparesis and orthostatic hypotension in LBD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"35 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BackgroundThe rising demand for alternative dementia assessments, fueled by healthcare workforce shortages and the growing population of individuals affected with dementia, necessitates innovative approaches to address accessibility, logistics, and diverse populations. The utilization of robots in cognitive assessments emerges as a promising solution, promising efficiency and engagement, while navigating the complex landscape of dementia care challenges.MethodExisting cognitive assessment tools were examined to develop a humanoid robot to deliver cognitive assessment. This robot‐assisted cognitive assessment development involved integrating artificial intelligence with robotic technology to create a comprehensive tool. Initially, the design phase included defining the cognitive domains to be assessed and tailoring the assessment tasks to suit robot‐human interaction. The robot’s programming incorporated adaptive features to respond to individual variations in cognitive abilities. Sensory modules, such as cameras and microphones, in the robot were integrated for real‐time data collection, enabling the robot to observe and interact with the individual. Iterative testing and refinement were performed to ensure the accuracy and reliability of the robot‐assisted cognitive assessment tool. Throughout the development process emphasis was on creating a robust and user‐friendly system that aligns with the nuanced nature of cognitive assessments for individuals affected by dementia.ResultRobot‐assisted cognitive assessments were tested in a nursing home setting, showing promising results and providing valuable insights into residents' cognitive functioning.ConclusionThe robot assisted assessments, integrated with AI, offer a comprehensive understanding of memory, attention, and other cognitive domains. The individual variability in cognitive abilities among residents is highlighted, enabling personalized care plans tailored to specific needs. The positive engagement and usability reported by residents suggest a potential avenue for integrating this technology into routine care practices. The real‐time data collection capabilities of the robot contribute to a more dynamic and accurate assessment of cognitive health. Caregivers benefit from the objective cognitive performance data, allowing for timely interventions and adjustments in care plans. The iterative feedback loop from residents and caregivers facilitates continuous improvement in the robot‐assisted cognitive assessment tool, making it a valuable and beneficial asset in enhancing the quality of care provided in nursing homes.
{"title":"Humanoid Robots perform cognitive assessments: to address healthcare worker shortages","authors":"Arshia A Khan","doi":"10.1002/alz.088116","DOIUrl":"https://doi.org/10.1002/alz.088116","url":null,"abstract":"BackgroundThe rising demand for alternative dementia assessments, fueled by healthcare workforce shortages and the growing population of individuals affected with dementia, necessitates innovative approaches to address accessibility, logistics, and diverse populations. The utilization of robots in cognitive assessments emerges as a promising solution, promising efficiency and engagement, while navigating the complex landscape of dementia care challenges.MethodExisting cognitive assessment tools were examined to develop a humanoid robot to deliver cognitive assessment. This robot‐assisted cognitive assessment development involved integrating artificial intelligence with robotic technology to create a comprehensive tool. Initially, the design phase included defining the cognitive domains to be assessed and tailoring the assessment tasks to suit robot‐human interaction. The robot’s programming incorporated adaptive features to respond to individual variations in cognitive abilities. Sensory modules, such as cameras and microphones, in the robot were integrated for real‐time data collection, enabling the robot to observe and interact with the individual. Iterative testing and refinement were performed to ensure the accuracy and reliability of the robot‐assisted cognitive assessment tool. Throughout the development process emphasis was on creating a robust and user‐friendly system that aligns with the nuanced nature of cognitive assessments for individuals affected by dementia.ResultRobot‐assisted cognitive assessments were tested in a nursing home setting, showing promising results and providing valuable insights into residents' cognitive functioning.ConclusionThe robot assisted assessments, integrated with AI, offer a comprehensive understanding of memory, attention, and other cognitive domains. The individual variability in cognitive abilities among residents is highlighted, enabling personalized care plans tailored to specific needs. The positive engagement and usability reported by residents suggest a potential avenue for integrating this technology into routine care practices. The real‐time data collection capabilities of the robot contribute to a more dynamic and accurate assessment of cognitive health. Caregivers benefit from the objective cognitive performance data, allowing for timely interventions and adjustments in care plans. The iterative feedback loop from residents and caregivers facilitates continuous improvement in the robot‐assisted cognitive assessment tool, making it a valuable and beneficial asset in enhancing the quality of care provided in nursing homes.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"84 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Occupational therapists (OTs) are among the health care professionals who assist individuals with neurocognitive disorders (NCDs) to engage in self‐care and leisure activities in a skilled nursing facility (SNF) environment. OTs use various environmental modifications to help individuals with NCDs engage in various activities (Jensen & Padilla, 2017). Strong evidence has been found to support occupational therapy recommendations and interventions in adapting the physical environment to support person centered care (Gitlin et al., 2010; Jensen & Padilla, 2017; Zimmerman et al., 2013). This session aims to share findings from a qualitative case study regarding the perspective of OTs and how they use the built physical environment to help individuals with NCDs is a SNF engage in self‐care and leisure related activities. Recommendations from this study include nonpharmacological‐based intervention strategies that incorporate the use of the built environment in a SNF to improve the quality of life for clients with a NCD.
{"title":"The Environment Matters: Perspectives on Using the Physical Environment in a Skilled Nursing Facility for Clients with Dementia","authors":"Jennie L DiGrado","doi":"10.1002/alz.089985","DOIUrl":"https://doi.org/10.1002/alz.089985","url":null,"abstract":"Occupational therapists (OTs) are among the health care professionals who assist individuals with neurocognitive disorders (NCDs) to engage in self‐care and leisure activities in a skilled nursing facility (SNF) environment. OTs use various environmental modifications to help individuals with NCDs engage in various activities (Jensen & Padilla, 2017). Strong evidence has been found to support occupational therapy recommendations and interventions in adapting the physical environment to support person centered care (Gitlin et al., 2010; Jensen & Padilla, 2017; Zimmerman et al., 2013). This session aims to share findings from a qualitative case study regarding the perspective of OTs and how they use the built physical environment to help individuals with NCDs is a SNF engage in self‐care and leisure related activities. Recommendations from this study include nonpharmacological‐based intervention strategies that incorporate the use of the built environment in a SNF to improve the quality of life for clients with a NCD.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"30 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936997","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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