Wooseok Jung, Chong Hyun Suh, Seung Hyun Lee, Jinyoung Kim, Dong‐Hee Kim, Hyeonwoo Cho, Yeha Lee, Sang Joon Kim
BackgroundNormative percentile (NP) quantifies brain atrophy by comparing regional brain volumes of a subject against age and sex‐matched cognitively normal populations. Accurate intracranial volume (ICV) adjustment is vital in NP quantification to minimize the effect of an individual’s head size. However, which intracranial volume adjustment method yields reliable normative percentiles remains unclear. This study explores the differences between ICV adjustment methods to compute NPs and their accuracy in atrophy quantification.MethodsWe sampled MRIs of 1261 subjects consecutively visited the memory clinic (932 MCI; 329 AD dementia) for memory concern and 275 from ADNI (150 MCI; 125 AD). We utilized the AI‐based ICV segmentation tool implemented in VUNO‐Med DeepBrain to measure ICV. We compared three ICV adjustment methods for the NP computation: raw volume, proportion, and residual approaches (Figure 2). To evaluate the reliability of NP, we gauged the correlation between left and right hippocampal NPs and their medial temporal lobe atrophy (MTA) scores manually annotated by two neuroradiologists with consensus. The cut‐off of the MTA score of each hemisphere is set to 2 for subjects with age < 75 and 3 otherwise.ResultsAll ICV adjustment methods effectively reduced correlation with ICV (correlations: raw volume = 0.32±0.10, proportion = ‐0.06±0.09, residual = ‐0.07±0.08), but there was no statistically significant difference between the correlations of the proportion and residual methods to ICV. Also, the proportion method retrieves larger hippocampal NP from patients with smaller ICV than the residual method in all disease stage groups. Plotting the mean normative percentiles against ICV volumes suggests that the raw volume method generates more reliable NPs to detect abnormalities in patients with smaller ICV, but using the proportion method was more effective in those with large ICV in both ADNI and ASAN datasets.ConclusionDifferent ICV adjustment methods generate distinct normative percentiles. Despite their effective head‐size correction, applying ICV adjustment was only more effective in subjects with larger ICV than average. Further research is required to confirm if this result applies to other brain regions.
{"title":"Comparison of intracranial volume adjustment methods to evaluate brain atrophy severity in AD continuum","authors":"Wooseok Jung, Chong Hyun Suh, Seung Hyun Lee, Jinyoung Kim, Dong‐Hee Kim, Hyeonwoo Cho, Yeha Lee, Sang Joon Kim","doi":"10.1002/alz.087186","DOIUrl":"https://doi.org/10.1002/alz.087186","url":null,"abstract":"BackgroundNormative percentile (NP) quantifies brain atrophy by comparing regional brain volumes of a subject against age and sex‐matched cognitively normal populations. Accurate intracranial volume (ICV) adjustment is vital in NP quantification to minimize the effect of an individual’s head size. However, which intracranial volume adjustment method yields reliable normative percentiles remains unclear. This study explores the differences between ICV adjustment methods to compute NPs and their accuracy in atrophy quantification.MethodsWe sampled MRIs of 1261 subjects consecutively visited the memory clinic (932 MCI; 329 AD dementia) for memory concern and 275 from ADNI (150 MCI; 125 AD). We utilized the AI‐based ICV segmentation tool implemented in VUNO‐Med DeepBrain to measure ICV. We compared three ICV adjustment methods for the NP computation: raw volume, proportion, and residual approaches (Figure 2). To evaluate the reliability of NP, we gauged the correlation between left and right hippocampal NPs and their medial temporal lobe atrophy (MTA) scores manually annotated by two neuroradiologists with consensus. The cut‐off of the MTA score of each hemisphere is set to 2 for subjects with age < 75 and 3 otherwise.ResultsAll ICV adjustment methods effectively reduced correlation with ICV (correlations: raw volume = 0.32±0.10, proportion = ‐0.06±0.09, residual = ‐0.07±0.08), but there was no statistically significant difference between the correlations of the proportion and residual methods to ICV. Also, the proportion method retrieves larger hippocampal NP from patients with smaller ICV than the residual method in all disease stage groups. Plotting the mean normative percentiles against ICV volumes suggests that the raw volume method generates more reliable NPs to detect abnormalities in patients with smaller ICV, but using the proportion method was more effective in those with large ICV in both ADNI and ASAN datasets.ConclusionDifferent ICV adjustment methods generate distinct normative percentiles. Despite their effective head‐size correction, applying ICV adjustment was only more effective in subjects with larger ICV than average. Further research is required to confirm if this result applies to other brain regions.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"2 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940039","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}
Polina Shichkova, Aida Kamalian, Marco Tognetti, Christopher Below, Roland Bruderer, Yuehan Feng, Michael W Lutz, Abhay Moghekar
BackgroundDespite age being the primary risk factor for Alzheimer's disease (AD), there remains a necessity for a thorough understanding of the distinct biological pathways affected in the course of healthy aging as opposed to the pathological aging that leads to neurodegeneration. As the genome remains constant throughout one's lifespan, it becomes crucial to unravel the impact of aging on the proteome. Proteins, being key players in various cellular functions, mediate the effects of environmental stimuli and epigenetic alterations. Moreover, despite the brain's protection by the blood‐brain barrier, emerging evidence suggests that systemic events like inflammation and metabolic dysfunction can significantly influence the risk of developing AD.MethodMatched CSF and plasma samples were obtained from individuals at the same visit from the Neurology Clinic and Alzheimer’s Disease Research Center at Johns Hopkins. Samples were collected from young control subjects (n= 53), and healthy elderly subjects (n = 40). The plasma samples were depleted in 96‐well format using an automated MARS‐14 depletion system. The depleted plasma and neat CSF samples were subsequently processed to tryptic peptides and analyzed using data‐independent acquisition (DIA)‐mass spectrometry (MS). Data processing and analysis were performed using Biognosys’ Spectronaut software.ResultUsing our optimized discovery workflow, we analyzed the above‐described cohort of 93 matched plasma and CSF sample pairs. This resulted in more than 73254 quantified peptides (associated with > 4000 proteins) in CSF and 62750 quantified peptides (associated with > 2500 proteins) in plasma. The depth and breadth of protein quantification cover numerous pathological mechanisms such as AB and Tau pathology, synaptic dysfunction, neuronal injury, iron toxicity and inflammation. Harnessing the unique feature of MS‐based proteomics, we focused on the identification of differentially regulated peptides that are located in protein regions where known events such as alternative splicing, truncation or protease cleavage occur.ConclusionThe peptide‐centric nature of our approach allowed us to assess a variety of post‐translational modifications, truncations and isoforms. We envision this unbiased profiling of proteoforms as a powerful tool to elucidate complex disease mechanisms.
{"title":"Quantitative dissection of healthy aging using protein and peptide signatures from paired CSF and plasma","authors":"Polina Shichkova, Aida Kamalian, Marco Tognetti, Christopher Below, Roland Bruderer, Yuehan Feng, Michael W Lutz, Abhay Moghekar","doi":"10.1002/alz.089108","DOIUrl":"https://doi.org/10.1002/alz.089108","url":null,"abstract":"BackgroundDespite age being the primary risk factor for Alzheimer's disease (AD), there remains a necessity for a thorough understanding of the distinct biological pathways affected in the course of healthy aging as opposed to the pathological aging that leads to neurodegeneration. As the genome remains constant throughout one's lifespan, it becomes crucial to unravel the impact of aging on the proteome. Proteins, being key players in various cellular functions, mediate the effects of environmental stimuli and epigenetic alterations. Moreover, despite the brain's protection by the blood‐brain barrier, emerging evidence suggests that systemic events like inflammation and metabolic dysfunction can significantly influence the risk of developing AD.MethodMatched CSF and plasma samples were obtained from individuals at the same visit from the Neurology Clinic and Alzheimer’s Disease Research Center at Johns Hopkins. Samples were collected from young control subjects (n= 53), and healthy elderly subjects (n = 40). The plasma samples were depleted in 96‐well format using an automated MARS‐14 depletion system. The depleted plasma and neat CSF samples were subsequently processed to tryptic peptides and analyzed using data‐independent acquisition (DIA)‐mass spectrometry (MS). Data processing and analysis were performed using Biognosys’ Spectronaut software.ResultUsing our optimized discovery workflow, we analyzed the above‐described cohort of 93 matched plasma and CSF sample pairs. This resulted in more than 73254 quantified peptides (associated with > 4000 proteins) in CSF and 62750 quantified peptides (associated with > 2500 proteins) in plasma. The depth and breadth of protein quantification cover numerous pathological mechanisms such as AB and Tau pathology, synaptic dysfunction, neuronal injury, iron toxicity and inflammation. Harnessing the unique feature of MS‐based proteomics, we focused on the identification of differentially regulated peptides that are located in protein regions where known events such as alternative splicing, truncation or protease cleavage occur.ConclusionThe peptide‐centric nature of our approach allowed us to assess a variety of post‐translational modifications, truncations and isoforms. We envision this unbiased profiling of proteoforms as a powerful tool to elucidate complex disease mechanisms.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"130 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940094","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}
Jesús Garcia Castro, Sara Rubio‐Guerra, Judit Selma González, Molly B Memel, Oriol Dols‐Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona‐Iragui, Isabel Barroeta, Miguel A Santos‐Santos, Mª Belen Sánchez‐Saudinós, Isabel Sala, Hilary W. Heuer, Adam M. Staffaroni, Kaitlin B. Casaletto, Brad F. Boeve, Adam L. Boxer, Howard J. Rosen, Alberto Lleo, Ignacio Illán‐Gala
BackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.
{"title":"Influence of biological sex on early cognitive performance in FTLD mutation carriers: an ALLFTD study","authors":"Jesús Garcia Castro, Sara Rubio‐Guerra, Judit Selma González, Molly B Memel, Oriol Dols‐Icardo, Alexandre Bejanin, Olivia Belbin, Juan Fortea, Daniel Alcolea, Maria Carmona‐Iragui, Isabel Barroeta, Miguel A Santos‐Santos, Mª Belen Sánchez‐Saudinós, Isabel Sala, Hilary W. Heuer, Adam M. Staffaroni, Kaitlin B. Casaletto, Brad F. Boeve, Adam L. Boxer, Howard J. Rosen, Alberto Lleo, Ignacio Illán‐Gala","doi":"10.1002/alz.088312","DOIUrl":"https://doi.org/10.1002/alz.088312","url":null,"abstract":"BackgroundAccumulating evidence indicates that biological sex may influence clinical manifestation within the spectrum of frontotemporal lobar degeneration (FTLD), implying differences in cognitive reserve. Nonetheless, investigations into the impact of biological sex during the preclinical and minimally symptomatic stages of FTLD are lacking.MethodWe included 275 mutation carriers (158 females; 127 with C9orf72, 68 with GRN, and 80 with MAPT mutations) and 161 non‐carrier familial controls (97 females) from the ALLFTD Consortium (Staffaroni et al., Nat Medicine 2022). Participants underwent magnetic resonance imaging (MRI; 348 baseline, 338 longitudinal) and neuropsychological evaluations (394 baseline, 507 longitudinal). Behavioral symptoms were characterized with the Revised Self‐Monitoring Scale (RSMS) and the Neuropsychiatric Inventory (NPI severity scores). MRI‐derived regional volume estimates (RVE) were computed. Cognitive measures and RVE were normalized against sex‐matched controls. Cognitive composites (language, executive function, and visuospatial function) were calculated by averaging raw scores for each domain. Clinical characteristics and RVE comparisons were made between male and female participants. We adopted the residuals approach to explore behavioral and cognitive reserve by fitting a linear regression model for executive z‐scores as the response value and age, education, and RVE as explanatory variables.ResultIn mutation carriers, sex was not a significant differentiator in age, education level, disease severity, or mutation frequency. Most mutation carriers (188, 68%) were asymptomatic or mildly symptomatic at baseline. However, female mutation carriers exhibited significantly lower visuospatial performance at baseline (Cohen's d = ‐0.34, 95% CI[‐0.58, ‐0.09], p=.001). This difference remained significant among asymptomatic GRN mutation carriers (Cohen’s d = ‐0.73, 95% CI[‐1.22, ‐0.23], p=0.003) but not in other mutations. Following the residuals approach, female mutation carriers showed higher executive performance than males for the same amount of both frontotemporal and global atrophy as quantified by RVE (Cohen's d=0.45, 95 % CI[0.22, 0.67], p<.001). The observed higher executive reserve in women was particularly pronounced in C9orf72 carriers (Cohen's d=0.77, 95% CI[0.35, 1.20], p<.001) but not significant in GRN (p=0.48) and MAPT carriers (p=0.07). No differences in behavioral reserve reached statistical significance.ConclusionFemale sex might modulate early cognitive performance and confer higher executive reserve in FTLD mutation carriers.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"16 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940153","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}
Bhuvanachandra Bhoopal, Brett M. Frye, Avinash Bansode, Mack Miller, Naresh Damuka, Krishna Kumar Gollepalli, Richard A. Barcus, Samuel N. Lockhart, Courtney L. Sutphen, Matthew J. Jorgensen, Suzanne Craft, Thomas C. Register, Christopher T Whitlow, Carol A. Shively, Kiran K. Solingapuram Sai
BackgroundOlder vervet monkeys are an excellent model for studying age‐associated Aβ deposition; however, they have high proportions of low‐affinity Aβ sites compared to human brains. Commonly used Aβ PET radiotracers are most useful in detecting high affinity Aβ fibrils. Measuring real‐time levels of low affinity Aβ fibrils through PET provides critical information of early AD progression. The radiotracer [18F]FC119S has high binding strength for Aβ1–42 protein aggregates (0.16 nM) and AD brain homogenates (13–15 nM). A pilot clinical trial showed significantly higher hippocampal and cortical uptake in AD patients over cognitively normal participants. Here we report the fully‐automated [18F]FC119S radiochemistry and preliminary imaging and fluid biomarker correlation data in aged vervet monkeys.MethodsRadiochemistry followed [18F]¯‐assisted nucleophilic substitution of mesityl precursor and deprotection of Boc group. [18F]FC119S(∼0.37GBq)‐based brain PET (0‐120min) and T1‐weighted whole‐brain MRI scans were conducted in aged vervets (19‐27 y, n=14). CSF and plasma Aβ40, Aβ42, pTau181, and NfL were measured in samples taken close to the time of PET. Standard Uptake Values with cerebellum as reference (SUVr) and time‐activity‐curves (TACs) were calculated from PET/MR (Figure 1). SUVrs of anterior and posterior cingulate, hippocampus, frontal, parietal, temporal, and occipital lobes were correlated with age, MRI outcomes (grey and white matter volumes), and fluid biomarker data.Results[18F]FC119S production was highly reproducible (n>25 runs) in high (>97%) radiochemical purities, and molar activities (∼140 GBq/µmol). TACs showed favorable washout kinetics from all brain regions. SUVrs of hippocampus and cortical parietal lobe positively correlated with age and SUVrs of all the regions analyzed negatively correlated with MRI deep gray and white matter volumes. Among the high SUVr regions, cortical anterior cingulate SUVr was highly positively correlated (Figure 2) with CSF pTau181 (r=0.78, **p=0.002).ConclusionPreliminary [18F]FC119S PET evaluations agrees with human PET data in vervets with high uptake in regions associated with Aβ deposition. Among all fluid biomarkers analyzed, CSF pTau181 was the best correlate of all the brain PET SUVrs. Association of Aβ PET imaging data with synaptic density and microtubule data in the same cohort is being evaluated to explore the potential neurodegeneration pathways in aged vervet monkeys.
{"title":"PET imaging utility of a novel Aβ‐tracking PET radiotracer, [18F]FC119S in aged vervet monkeys","authors":"Bhuvanachandra Bhoopal, Brett M. Frye, Avinash Bansode, Mack Miller, Naresh Damuka, Krishna Kumar Gollepalli, Richard A. Barcus, Samuel N. Lockhart, Courtney L. Sutphen, Matthew J. Jorgensen, Suzanne Craft, Thomas C. Register, Christopher T Whitlow, Carol A. Shively, Kiran K. Solingapuram Sai","doi":"10.1002/alz.089843","DOIUrl":"https://doi.org/10.1002/alz.089843","url":null,"abstract":"BackgroundOlder vervet monkeys are an excellent model for studying age‐associated Aβ deposition; however, they have high proportions of low‐affinity Aβ sites compared to human brains. Commonly used Aβ PET radiotracers are most useful in detecting high affinity Aβ fibrils. Measuring real‐time levels of low affinity Aβ fibrils through PET provides critical information of early AD progression. The radiotracer [<jats:sup>18</jats:sup>F]FC119S has high binding strength for Aβ<jats:sub>1–42</jats:sub> protein aggregates (0.16 nM) and AD brain homogenates (13–15 nM). A pilot clinical trial showed significantly higher hippocampal and cortical uptake in AD patients over cognitively normal participants. Here we report the fully‐automated [<jats:sup>18</jats:sup>F]FC119S radiochemistry and preliminary imaging and fluid biomarker correlation data in aged vervet monkeys.MethodsRadiochemistry followed [<jats:sup>18</jats:sup>F]<jats:sup>¯</jats:sup>‐assisted nucleophilic substitution of mesityl precursor and deprotection of Boc group. [<jats:sup>18</jats:sup>F]FC119S(∼0.37GBq)‐based brain PET (0‐120min) and T1‐weighted whole‐brain MRI scans were conducted in aged vervets (19‐27 y, n=14). CSF and plasma Aβ<jats:sub>40</jats:sub>, Aβ<jats:sub>42</jats:sub>, pTau181, and NfL were measured in samples taken close to the time of PET. Standard Uptake Values with cerebellum as reference (SUVr) and time‐activity‐curves (TACs) were calculated from PET/MR (Figure 1). SUVrs of anterior and posterior cingulate, hippocampus, frontal, parietal, temporal, and occipital lobes were correlated with age, MRI outcomes (grey and white matter volumes), and fluid biomarker data.Results[<jats:sup>18</jats:sup>F]FC119S production was highly reproducible (n>25 runs) in high (>97%) radiochemical purities, and molar activities (∼140 GBq/µmol). TACs showed favorable washout kinetics from all brain regions. SUVrs of hippocampus and cortical parietal lobe positively correlated with age and SUVrs of all the regions analyzed negatively correlated with MRI deep gray and white matter volumes. Among the high SUVr regions, cortical anterior cingulate SUVr was highly positively correlated (Figure 2) with CSF pTau181 (r=0.78, **p=0.002).ConclusionPreliminary [<jats:sup>18</jats:sup>F]FC119S PET evaluations agrees with human PET data in vervets with high uptake in regions associated with Aβ deposition. Among all fluid biomarkers analyzed, CSF pTau181 was the best correlate of all the brain PET SUVrs. Association of Aβ PET imaging data with synaptic density and microtubule data in the same cohort is being evaluated to explore the potential neurodegeneration pathways in aged vervet monkeys.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"24 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940155","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}
Jane E Alty, Xinyi Wang, Aidan Bindoff, Rebecca J St George, Eddy Roccati, Larissa Bartlett, Katherine Lawler, Alastair J Noyce, Son Tran, Anna E King, Quan Bai, James C Vickers
BackgroundFinding low‐cost, accessible methods to detect people with early‐stage Alzheimer’s disease is a research priority for neuroprotective drug development. Subtle motor impairment of gait occurs years before episodic memory decline but there has been little investigation of whether self‐administered hand motor tests can detect this pre‐symptomatic period. This study evaluated how home‐based unsupervised keyboard tapping tests from the TAS Test protocol predict episodic memory performance in a sample of older adults without overt cognitive impairment, as a potential indicative measure of early Alzheimer’s disease.Method1,140 community participants (65.7 ± 7.4 years old; 73% female) without cognitive impairment from the ISLAND cohort study completed a 40‐second single key tapping test, a 60‐second alternate key tapping test, and a 40‐second sequence tapping test from TAS Test. Participants also completed validated CANTAB cognitive tests of episodic memory, working memory and executive function. Frequency, variability, key press duration and accuracy scores were calculated for each tapping test. Generalized linear models examined associations between keyboard tapping and cognitive performance, adjusted for confounders including age, sex, depression, anxiety and education.ResultCombination of motor features of the single key (R2adj = 8.0%, ΔAIC = 3.7), alternate key (R2adj = 7.9%, ΔAIC = 2.8), and sequence tapping tests (R2adj = 8.2%, ΔAIC = 8.4) improved estimation of episodic memory performance relative to models with demographic and mood confounders only (R2adj = 7.3%). Only tapping features of tests involving sequence tapping (R2adj = 6.3%, ΔAIC = 2.5) improved estimation of working memory. Tapping features of single key tapping tests (R2adj = 15.8%, ΔAIC = 8.3) and sequence tapping tests (R2adj =16.5%, ΔAIC = 13.7) improved the estimation of executive function performance.ConclusionBrief unsupervised and self‐administered online keyboard tapping tests predict asymptomatic episodic memory decline in a sample of older adults. This provides a potential low‐cost and brief home‐based method for risk stratification of enriched cohorts for further assessment.
{"title":"Using TAS Test online hand‐tapping tests to detect cognitive decline in a large community cohort of older Australians","authors":"Jane E Alty, Xinyi Wang, Aidan Bindoff, Rebecca J St George, Eddy Roccati, Larissa Bartlett, Katherine Lawler, Alastair J Noyce, Son Tran, Anna E King, Quan Bai, James C Vickers","doi":"10.1002/alz.091929","DOIUrl":"https://doi.org/10.1002/alz.091929","url":null,"abstract":"BackgroundFinding low‐cost, accessible methods to detect people with early‐stage Alzheimer’s disease is a research priority for neuroprotective drug development. Subtle motor impairment of gait occurs years before episodic memory decline but there has been little investigation of whether self‐administered hand motor tests can detect this pre‐symptomatic period. This study evaluated how home‐based unsupervised keyboard tapping tests from the TAS Test protocol predict episodic memory performance in a sample of older adults without overt cognitive impairment, as a potential indicative measure of early Alzheimer’s disease.Method1,140 community participants (65.7 ± 7.4 years old; 73% female) without cognitive impairment from the ISLAND cohort study completed a 40‐second single key tapping test, a 60‐second alternate key tapping test, and a 40‐second sequence tapping test from TAS Test. Participants also completed validated CANTAB cognitive tests of episodic memory, working memory and executive function. Frequency, variability, key press duration and accuracy scores were calculated for each tapping test. Generalized linear models examined associations between keyboard tapping and cognitive performance, adjusted for confounders including age, sex, depression, anxiety and education.ResultCombination of motor features of the single key (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 8.0%, ΔAIC = 3.7), alternate key (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 7.9%, ΔAIC = 2.8), and sequence tapping tests (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 8.2%, ΔAIC = 8.4) improved estimation of episodic memory performance relative to models with demographic and mood confounders only (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 7.3%). Only tapping features of tests involving sequence tapping (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 6.3%, ΔAIC = 2.5) improved estimation of working memory. Tapping features of single key tapping tests (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> = 15.8%, ΔAIC = 8.3) and sequence tapping tests (R<jats:sup>2</jats:sup> <jats:sub>adj</jats:sub> =16.5%, ΔAIC = 13.7) improved the estimation of executive function performance.ConclusionBrief unsupervised and self‐administered online keyboard tapping tests predict asymptomatic episodic memory decline in a sample of older adults. This provides a potential low‐cost and brief home‐based method for risk stratification of enriched cohorts for further assessment.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"2 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940159","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}
Maryam Naseri, Owen T. Carmichael, Sreekrishna R. Pillai
BackgroundWhile a great deal of recent effort has focused on addressing a perceived reproducibility crisis within brain structural magnetic resonance imaging (MRI) and functional MRI research communities, less attention has been paid to reproducibility of brain positron emission tomography (PET) research.MethodsWe examined the current landscape of factors that contribute to reproducible neuroimaging data analysis, comparing brain MRI to brain PET. The factors included scientific standards, analytic plan pre‐registration, data and code sharing, containerized workflows, and standardized processing pipelines. To demonstrate the positive impact that further developing such reproducibility factors would have on brain PET research, we conducted one case study in which the brain PET processing pipeline developed for one flagship study (Alzheimer's Disease Neuroimaging Initiative, ADNI) for brain 18F‐florbetapir and 18F‐fluorodeoxyglucose (FDG) analysis was reproduced in our laboratory.ResultsCompared to fMRI, PET research encounters substantial challenges in adopting essential reproducibility practices. While 85% of fMRI studies adhere to the standardized reporting practices, PET is in the early stages of establishing reporting practices, lacking a standardized checklist. Pre‐registration is prevalent for fMRI (57.6%) but notably absent in PET, with no pre‐registered PET studies found on platforms such as the Center for Open Science. The number of shared datasets is higher for fMRI compared to PET, with 92 fMRI datasets and only 9 PET datasets on repositories like OpenNeuro. Moreover, there are very few data repositories for newer PET radiotracers. Containerized software availability also favor fMRI, with platforms like (Brain Imaging Data Structure, BIDS) apps hosting 66% dedicated fMRI tools, while no PET‐specific software is available. Standardized processing pipelines follow the same trend, with fMRI boasting optimized workflows for specific protocols, while PET has few dedicated pipelines and lacks validation studies for existing options. Furthermore, while our case study demonstrated excellent correlation results for both the 18F‐FDG and 18F‐florbetapir methods (Figure 2), the replication of the ADNI PET pipeline posed substantial challenges and implementation delays. These obstacles and delays in execution were due to incomplete documentation and ambiguities in application details.ConclusionPET neuroimaging lags behind its MRI‐related counterparts in achieving robust reproducibility.
{"title":"Reproducibility Challenges in Brain PET Data Analysis","authors":"Maryam Naseri, Owen T. Carmichael, Sreekrishna R. Pillai","doi":"10.1002/alz.089280","DOIUrl":"https://doi.org/10.1002/alz.089280","url":null,"abstract":"BackgroundWhile a great deal of recent effort has focused on addressing a perceived reproducibility crisis within brain structural magnetic resonance imaging (MRI) and functional MRI research communities, less attention has been paid to reproducibility of brain positron emission tomography (PET) research.MethodsWe examined the current landscape of factors that contribute to reproducible neuroimaging data analysis, comparing brain MRI to brain PET. The factors included scientific standards, analytic plan pre‐registration, data and code sharing, containerized workflows, and standardized processing pipelines. To demonstrate the positive impact that further developing such reproducibility factors would have on brain PET research, we conducted one case study in which the brain PET processing pipeline developed for one flagship study (Alzheimer's Disease Neuroimaging Initiative, ADNI) for brain 18F‐florbetapir and 18F‐fluorodeoxyglucose (FDG) analysis was reproduced in our laboratory.ResultsCompared to fMRI, PET research encounters substantial challenges in adopting essential reproducibility practices. While 85% of fMRI studies adhere to the standardized reporting practices, PET is in the early stages of establishing reporting practices, lacking a standardized checklist. Pre‐registration is prevalent for fMRI (57.6%) but notably absent in PET, with no pre‐registered PET studies found on platforms such as the Center for Open Science. The number of shared datasets is higher for fMRI compared to PET, with 92 fMRI datasets and only 9 PET datasets on repositories like OpenNeuro. Moreover, there are very few data repositories for newer PET radiotracers. Containerized software availability also favor fMRI, with platforms like (Brain Imaging Data Structure, BIDS) apps hosting 66% dedicated fMRI tools, while no PET‐specific software is available. Standardized processing pipelines follow the same trend, with fMRI boasting optimized workflows for specific protocols, while PET has few dedicated pipelines and lacks validation studies for existing options. Furthermore, while our case study demonstrated excellent correlation results for both the 18F‐FDG and 18F‐florbetapir methods (Figure 2), the replication of the ADNI PET pipeline posed substantial challenges and implementation delays. These obstacles and delays in execution were due to incomplete documentation and ambiguities in application details.ConclusionPET neuroimaging lags behind its MRI‐related counterparts in achieving robust reproducibility.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"38 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940221","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}
Katherine Cullen, Emilie V Brotherhood, Deborah Fitzsimmons, Joshua Stott
BackgroundNon‐memory‐led dementias pose additional challenges to ‘typical dementias’ including unusual symptoms and younger onset leading to particularly high neuropsychiatric comorbidities. As part of the economic evaluation supporting the RD‐talk research programme, we require the collection of participant level resource use associated with the intervention compared with usual care. The resource use measure (RUM) needs to be sufficiently comprehensive, but still focused to capture the key items of interest (e.g., main drivers of resource use and associated cost) to balance the trade‐off between precision, effort, and burden to research participant.MethodInitial discussion with carers of people with non‐memory‐led dementia and clinical experts informed a draft list of resource items to design a RUM. A modified Delphi survey was carried out with informal carers and healthcare professionals (HCPs). Consensus of each item, using pre‐defined levels to keep or remove items, was summarised using descriptive statistics and percentage agreement. Inter‐rater reliability between rounds was assessed using the intra‐class correlation coefficient; the stability of the raters’ responses was assessed with the Wilcoxon signed rank test.ResultFor round one, 18 participants were recruited (11 HCPs, 9 carers), 14 participants remained for round two (7 HCPs, 7 carers). For primary/community care, general practitioner appointments, psychological interventions (such as talking therapy), and rare dementia support groups or direct calls were all highly rated by both HCPs and carers. The RUM should include time taken off work or taking early retirement due to caring for someone with rare dementia. Categories of caring tasks were listed, from personal care and physical help, to helping with paperwork, financial matters, dealing with care services and benefits, and managing challenging behaviour. All categories were highly rated by HCPs and carers.ConclusionResource use measures are mainly designed for the person with a disease or condition and focus on health and social care use. There can be a considerable burden on informal carers when someone is diagnosed with rare dementia, and it is important to capture key resource items in addition to health and social care relevant to this population when evaluating interventions in rare dementia management.
{"title":"Development of the set of resource use items to capture costs related to informal care for people with Rare Dementia for RD‐TALK","authors":"Katherine Cullen, Emilie V Brotherhood, Deborah Fitzsimmons, Joshua Stott","doi":"10.1002/alz.092682","DOIUrl":"https://doi.org/10.1002/alz.092682","url":null,"abstract":"BackgroundNon‐memory‐led dementias pose additional challenges to ‘typical dementias’ including unusual symptoms and younger onset leading to particularly high neuropsychiatric comorbidities. As part of the economic evaluation supporting the RD‐talk research programme, we require the collection of participant level resource use associated with the intervention compared with usual care. The resource use measure (RUM) needs to be sufficiently comprehensive, but still focused to capture the key items of interest (e.g., main drivers of resource use and associated cost) to balance the trade‐off between precision, effort, and burden to research participant.MethodInitial discussion with carers of people with non‐memory‐led dementia and clinical experts informed a draft list of resource items to design a RUM. A modified Delphi survey was carried out with informal carers and healthcare professionals (HCPs). Consensus of each item, using pre‐defined levels to keep or remove items, was summarised using descriptive statistics and percentage agreement. Inter‐rater reliability between rounds was assessed using the intra‐class correlation coefficient; the stability of the raters’ responses was assessed with the Wilcoxon signed rank test.ResultFor round one, 18 participants were recruited (11 HCPs, 9 carers), 14 participants remained for round two (7 HCPs, 7 carers). For primary/community care, general practitioner appointments, psychological interventions (such as talking therapy), and rare dementia support groups or direct calls were all highly rated by both HCPs and carers. The RUM should include time taken off work or taking early retirement due to caring for someone with rare dementia. Categories of caring tasks were listed, from personal care and physical help, to helping with paperwork, financial matters, dealing with care services and benefits, and managing challenging behaviour. All categories were highly rated by HCPs and carers.ConclusionResource use measures are mainly designed for the person with a disease or condition and focus on health and social care use. There can be a considerable burden on informal carers when someone is diagnosed with rare dementia, and it is important to capture key resource items in addition to health and social care relevant to this population when evaluating interventions in rare dementia management.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"26 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940294","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}
BackgroundTraining programmes and workshops for Early Career Researchers (ECR) in dementia research are frequently expensive and inaccessible. This means that under resourced institutions, researchers and countries (LMIC) are unable to provide adequate training facilities for researchers focused on analyses for dementia outcomes. The result is that only elite institutions are provided high level training facilities for their researchers and those who are not represented in these institutions are underrepresented. Dementias Platform UK (DPUK) provides free and affordable training opportunities for all academic and industry researchers across the world.MethodThe DPUK training programme includes:1. Datathon workshops which enable researchers from across the world to access large cohort datasets on the DPUK Data Portal and work alongside other global researchers on a dementia‐focused research question.2. Academies for both elementary and advanced longitudinal data analysis are conducted twice a year.3. A 12‐week mentoring programme is provided after the Datathon workshop ‐ led by DPUK and aimed at producing a publishable output from their Datathon attendance.ResultOver 200 researchers across 11 countries have attended the DPUK Training events over the last 5 years.ConclusionProviding affordable or free training for the current and next generation of ECRs is possible by using the resources provided by a Trusted Research Environment (TRE) such as DPUK.
{"title":"Democratising Early Career Researcher (ECR) Training for Dementia Research","authors":"Sarah Bauermeister","doi":"10.1002/alz.093305","DOIUrl":"https://doi.org/10.1002/alz.093305","url":null,"abstract":"BackgroundTraining programmes and workshops for Early Career Researchers (ECR) in dementia research are frequently expensive and inaccessible. This means that under resourced institutions, researchers and countries (LMIC) are unable to provide adequate training facilities for researchers focused on analyses for dementia outcomes. The result is that only elite institutions are provided high level training facilities for their researchers and those who are not represented in these institutions are underrepresented. Dementias Platform UK (DPUK) provides free and affordable training opportunities for all academic and industry researchers across the world.MethodThe DPUK training programme includes:1. Datathon workshops which enable researchers from across the world to access large cohort datasets on the DPUK Data Portal and work alongside other global researchers on a dementia‐focused research question.2. Academies for both elementary and advanced longitudinal data analysis are conducted twice a year.3. A 12‐week mentoring programme is provided after the Datathon workshop ‐ led by DPUK and aimed at producing a publishable output from their Datathon attendance.ResultOver 200 researchers across 11 countries have attended the DPUK Training events over the last 5 years.ConclusionProviding affordable or free training for the current and next generation of ECRs is possible by using the resources provided by a Trusted Research Environment (TRE) such as DPUK.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"14 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142940416","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}
BackgroundTo explore the correlation between the topography of EPVS and cognitive impairment after aSAH.MethodPatients clinically diagnosed as aSAH by DSA and CT; Head magnetic resonance imaging was performed between 1 week and 1 month after onset, combined with clinical and neuroimaging variables to assess the incidence of hydrocephalus and delayed cerebral ischemia after aneurystic subarachnoid hemorrhage. Follow‐up was performed at 3 months, and the patients' prognosis and cognitive function were evaluated by mRS and the Montreal Cognitive Assesement (MoCA), respectively. The clinical characteristics of aSAH patients with EPVS <10 and EPVSV10 in basal ganglia and centrum semioval were compared, and a binary Logistic regression model was used to study the severity of EPVS and its correlation with DCI, subacute hydrocephalus, poor prognosis and cognitive impairment.ResultBG‐EPVS predominance pattern (BG‐EPVS > CSO‐EPVS) was more common in the aSAH group (53.8%) than in other primary SAH patients without aneurysm(15.8%). A total of 159 patients completed 3‐month MoCA assessment, of which 63 (39.6%) were diagnosed with cognitive impairment (MoCA<22). EPVS >10 (no matter CSO or BG) was associated with unfavorable functional outcomes at 3 months. BG‐EPVS >10 linked to subacute hydrocephalus and DCI, but not with cognitive impairment after adjusting for established predictors. In contrast, CSO‐EPVS>10 predicted worse cognitive function after adjustment for established variables.ConclusionCSO‐EPVS is associated with cognitive impair beyond aSAH, but not with subacute hydrocephalus and DCI, suggesting distinct lymphatic drainage and mechanism after an attack of aSAH.
{"title":"Topography and Predictitve Value of Enlarged Perivascular Spaces in Patients with Cognitive Impairment beyond Aneurysmal Subarachnoid Hemorrhage","authors":"Li Gong, Xueyuan Liu","doi":"10.1002/alz.094734","DOIUrl":"https://doi.org/10.1002/alz.094734","url":null,"abstract":"BackgroundTo explore the correlation between the topography of EPVS and cognitive impairment after aSAH.MethodPatients clinically diagnosed as aSAH by DSA and CT; Head magnetic resonance imaging was performed between 1 week and 1 month after onset, combined with clinical and neuroimaging variables to assess the incidence of hydrocephalus and delayed cerebral ischemia after aneurystic subarachnoid hemorrhage. Follow‐up was performed at 3 months, and the patients' prognosis and cognitive function were evaluated by mRS and the Montreal Cognitive Assesement (MoCA), respectively. The clinical characteristics of aSAH patients with EPVS <10 and EPVSV10 in basal ganglia and centrum semioval were compared, and a binary Logistic regression model was used to study the severity of EPVS and its correlation with DCI, subacute hydrocephalus, poor prognosis and cognitive impairment.ResultBG‐EPVS predominance pattern (BG‐EPVS > CSO‐EPVS) was more common in the aSAH group (53.8%) than in other primary SAH patients without aneurysm(15.8%). A total of 159 patients completed 3‐month MoCA assessment, of which 63 (39.6%) were diagnosed with cognitive impairment (MoCA<22). EPVS >10 (no matter CSO or BG) was associated with unfavorable functional outcomes at 3 months. BG‐EPVS >10 linked to subacute hydrocephalus and DCI, but not with cognitive impairment after adjusting for established predictors. In contrast, CSO‐EPVS>10 predicted worse cognitive function after adjustment for established variables.ConclusionCSO‐EPVS is associated with cognitive impair beyond aSAH, but not with subacute hydrocephalus and DCI, suggesting distinct lymphatic drainage and mechanism after an attack of aSAH.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"28 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936633","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}
Kristin R Wildsmith, Pallavi Sachdev, Kanta Horie, Larisa Reyderman, Arnaud Charil, Michio Kanekiyo, Han Yin, David Li, Akihiko Koyama, Shobha Dhadda, Michael C. Irizarry, Lynn D Kramer
BackgroundLecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau243) is an emerging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) [Horie et al. Nat Med. 2023;29:1954‐1963]. In order to evaluate effects of lecanemab on MTBR‐tau243, CSF was analyzed in a subset of early AD participants from the phase 3 (Clarity AD) trial.MethodCSF from n = 167 early AD participants from Clarity AD was analyzed using an IP‐MS based method [Horie et al. Nat Med. 2023;29:1954‐1963.]. Pearson correlation analysis was performed to assess relationships between CSF MTBR‐tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.ResultBaseline correlation analysis show that CSF MTBR‐tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1‐6, whole cortical grey (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptau181, total tau, neurogranin, NfL, Aβ40 and Aβ42; plasma markers: pTau217, pTau181, Aβ42/40, NfL and GFAP). CSF MTBR‐tau243 has a higher correlation with Tau PET SUVR (r = 0.74, WCGROI) vs. amyloid PET Centiloids (r = 0.39, WCG ROI). Levels of CSF MTBR‐tau243 increased over time in early AD (placebo). Treatment with lecanemab slowed the rate of increase of MTBR‐tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). While the results have limitations due to sample size and do not reach statistical significance, at 18 months lecanemab slowed the rate of increase in CSF MTBR‐tau243 by 44% vs. placebo.ConclusionThese results support that CSF MTBR‐tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab‐associated amyloid removal slows the formation of tau pathology in the brain.
{"title":"Lecanemab Slows Amyloid‐Induced Tau Pathology as Supported by CSF MTBR‐tau243 in Clarity AD","authors":"Kristin R Wildsmith, Pallavi Sachdev, Kanta Horie, Larisa Reyderman, Arnaud Charil, Michio Kanekiyo, Han Yin, David Li, Akihiko Koyama, Shobha Dhadda, Michael C. Irizarry, Lynn D Kramer","doi":"10.1002/alz.095507","DOIUrl":"https://doi.org/10.1002/alz.095507","url":null,"abstract":"BackgroundLecanemab is a humanized immunoglobulin G1 monoclonal antibody targeting neurotoxic Aβ protofibrils and Aβ plaques, which reduces markers of amyloid and significantly slows clinical decline on multiple cognition and function measures. Cerebrospinal fluid (CSF) microtubule‐binding region (MTBR) of tau containing the residue 243 (MTBR‐tau243) is an emerging tau pathology biomarker that tracks with tangle formation in Alzheimer’s disease (AD) [Horie et al. Nat Med. 2023;29:1954‐1963]. In order to evaluate effects of lecanemab on MTBR‐tau243, CSF was analyzed in a subset of early AD participants from the phase 3 (Clarity AD) trial.MethodCSF from n = 167 early AD participants from Clarity AD was analyzed using an IP‐MS based method [Horie et al. Nat Med. 2023;29:1954‐1963.]. Pearson correlation analysis was performed to assess relationships between CSF MTBR‐tau243, AD fluid biomarkers, amyloid PET and tau PET SUVR in multiple regions of interest. Mixed model for repeated measures was used to analyze change from baseline and assess treatment effect over 18 months.ResultBaseline correlation analysis show that CSF MTBR‐tau243 has the highest correlation with Tau PET SUVR across regions of interest (ROI) (Braak 1‐6, whole cortical grey (WCG) vs. all other fluid biomarkers assessed (CSF markers: ptau181, total tau, neurogranin, NfL, Aβ40 and Aβ42; plasma markers: pTau217, pTau181, Aβ42/40, NfL and GFAP). CSF MTBR‐tau243 has a higher correlation with Tau PET SUVR (r = 0.74, WCGROI) vs. amyloid PET Centiloids (r = 0.39, WCG ROI). Levels of CSF MTBR‐tau243 increased over time in early AD (placebo). Treatment with lecanemab slowed the rate of increase of MTBR‐tau243 vs. placebo, with a greater separation from placebo observed at 18 month (77 weeks) vs. 12 months (53 weeks). While the results have limitations due to sample size and do not reach statistical significance, at 18 months lecanemab slowed the rate of increase in CSF MTBR‐tau243 by 44% vs. placebo.ConclusionThese results support that CSF MTBR‐tau243 is a specific biomarker of tau tangle pathology and are consistent with the effects of lecanemab on Tau PET, which similarly showed a slowing of tau accumulation vs. placebo. These results demonstrate that lecanemab‐associated amyloid removal slows the formation of tau pathology in the brain.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"12 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936706","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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