Hasan Ishtayeh,Elena Battistoni,Sharon Pochtar,Tyne L M McHugh,Kizito-Tshitoko Tshilenge,Brian Rossmiller,Fatima Amer-Sarsour,Yevgeny Berdichevsky,Noam Muchtar,Miguel Weil,Lisa M Ellerby,Avraham Ashkenazi
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a well-characterized genetic etiology of a CAG expansion mutation in the huntingtin (HTT) gene, yet it remains without a cure. The hallmark of HD is the accumulation of intraneuronal aggregates of mutant HTT protein and polyglutamine (polyQ)-containing fragments, which cause impaired proteostasis and is an important HD therapeutic target. Aggregate-prone protein clearance primarily occurs through the autophagy-lysosome pathway and the ubiquitin-proteasome system, both of which can be modulated by deubiquitinating enzymes (DUBs). This study investigates the role of the DUB ubiquitin C-terminal hydrolase L3 (UCHL3) in modulating polyQ-mediated aggregation and toxicity. UCHL3 has previously been identified as a potential therapeutic target in cancer. We utilize HD models, including primary mouse neurons, patient fibroblasts, and patient-derived medium spiny neurons (MSN), which are the most vulnerable to HTT polyQ toxicity. Genetic lowering of UCHL3 decreased polyQ aggregates and increased autophagosome-lysosome fusion events. This was accompanied by STAT3 induction, which protects against neuronal proteotoxic stress. Furthermore, treatment with a small-molecule inhibitor of UCHL3 recapitulated the effects of UCHL3 lowering and attenuated pathological markers in HD MSN. These results provide a foundation for further exploration of UCHL3 inhibitors in the context of HD and underscore the biological connection between cancer and neurodegeneration for drug repurposing strategies.
{"title":"Targeting UCHL3 attenuates pathological markers in neuronal models of Huntington's disease.","authors":"Hasan Ishtayeh,Elena Battistoni,Sharon Pochtar,Tyne L M McHugh,Kizito-Tshitoko Tshilenge,Brian Rossmiller,Fatima Amer-Sarsour,Yevgeny Berdichevsky,Noam Muchtar,Miguel Weil,Lisa M Ellerby,Avraham Ashkenazi","doi":"10.1093/brain/awag028","DOIUrl":"https://doi.org/10.1093/brain/awag028","url":null,"abstract":"Huntington's disease (HD) is an autosomal dominant neurodegenerative disease with a well-characterized genetic etiology of a CAG expansion mutation in the huntingtin (HTT) gene, yet it remains without a cure. The hallmark of HD is the accumulation of intraneuronal aggregates of mutant HTT protein and polyglutamine (polyQ)-containing fragments, which cause impaired proteostasis and is an important HD therapeutic target. Aggregate-prone protein clearance primarily occurs through the autophagy-lysosome pathway and the ubiquitin-proteasome system, both of which can be modulated by deubiquitinating enzymes (DUBs). This study investigates the role of the DUB ubiquitin C-terminal hydrolase L3 (UCHL3) in modulating polyQ-mediated aggregation and toxicity. UCHL3 has previously been identified as a potential therapeutic target in cancer. We utilize HD models, including primary mouse neurons, patient fibroblasts, and patient-derived medium spiny neurons (MSN), which are the most vulnerable to HTT polyQ toxicity. Genetic lowering of UCHL3 decreased polyQ aggregates and increased autophagosome-lysosome fusion events. This was accompanied by STAT3 induction, which protects against neuronal proteotoxic stress. Furthermore, treatment with a small-molecule inhibitor of UCHL3 recapitulated the effects of UCHL3 lowering and attenuated pathological markers in HD MSN. These results provide a foundation for further exploration of UCHL3 inhibitors in the context of HD and underscore the biological connection between cancer and neurodegeneration for drug repurposing strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"42 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033856","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}
Ruby A Holland, Kelly M Smith, Isabel B Bleimeister, Jeffrey J Okoro, Samantha A Sherman, Ava V Zoltanski, Michael C Chiang, BaDoi N Phan, Bryan M Hooks, Andreas R Pfenning, Eileen K Nguyen, Sarah E Ross
Opioid withdrawal is a common and distressing manifestation of opioid dependence which, if left untreated, frequently results in relapse, accidental overdose, and suicide. While much is known about the role of mesolimbic and mesocortical dopaminergic neurons in mu opioid receptor-mediated reward, much less is understood about the impact of chronic opioid use on parallel aversive pathways mediated by the kappa opioid receptor and its endogenous ligand dynorphin. In the present study, we interrogate kappa opioid receptor-expressing ventral tegmental area neurons and their dynorphinergic inputs in vitro and in vivo, to elucidate the circuit mechanisms by which chronic opioids promote withdrawal behaviors in mice. Through a combination of genetic, molecular, and custom machine learning analytical approaches, we uncovered the effects of chronic morphine on kappa opioid receptor mRNA expression in the ventral tegmental area as well as dynorphin mRNA expression in several retrogradely traced dynorphinergic input regions. We find that chronic morphine exposure diminishes opioid-induced c-Fos expression selectively in midbrain kappa opioid receptor-expressing neurons. In addition, chemogenetic activation of kappa opioid receptor-expressing ventral tegmental area neurons was sufficient to attenuate diverse opioid withdrawal-associated behaviors, negative affect, and gastrointestinal distress in mice. Finally, we uncovered a glutamatergic subpopulation of kappa opioid receptor-expressing ventral tegmental area neurons projecting to the ventrolateral periaqueductal gray which, when activated, selectively relieved opioid withdrawal-associated gastrointestinal distress. These discoveries highlight a critical role for midbrain kappa opioid receptor-expressing neurons and the downstream ventrolateral periaqueductal gray in opioid withdrawal-associated disruption of hedonic homeostasis and gastrointestinal regulation.
{"title":"Tegmental kappa-opioid receptor neurons modulate opioid withdrawal via the periaqueductal gray","authors":"Ruby A Holland, Kelly M Smith, Isabel B Bleimeister, Jeffrey J Okoro, Samantha A Sherman, Ava V Zoltanski, Michael C Chiang, BaDoi N Phan, Bryan M Hooks, Andreas R Pfenning, Eileen K Nguyen, Sarah E Ross","doi":"10.1093/brain/awaf470","DOIUrl":"https://doi.org/10.1093/brain/awaf470","url":null,"abstract":"Opioid withdrawal is a common and distressing manifestation of opioid dependence which, if left untreated, frequently results in relapse, accidental overdose, and suicide. While much is known about the role of mesolimbic and mesocortical dopaminergic neurons in mu opioid receptor-mediated reward, much less is understood about the impact of chronic opioid use on parallel aversive pathways mediated by the kappa opioid receptor and its endogenous ligand dynorphin. In the present study, we interrogate kappa opioid receptor-expressing ventral tegmental area neurons and their dynorphinergic inputs in vitro and in vivo, to elucidate the circuit mechanisms by which chronic opioids promote withdrawal behaviors in mice. Through a combination of genetic, molecular, and custom machine learning analytical approaches, we uncovered the effects of chronic morphine on kappa opioid receptor mRNA expression in the ventral tegmental area as well as dynorphin mRNA expression in several retrogradely traced dynorphinergic input regions. We find that chronic morphine exposure diminishes opioid-induced c-Fos expression selectively in midbrain kappa opioid receptor-expressing neurons. In addition, chemogenetic activation of kappa opioid receptor-expressing ventral tegmental area neurons was sufficient to attenuate diverse opioid withdrawal-associated behaviors, negative affect, and gastrointestinal distress in mice. Finally, we uncovered a glutamatergic subpopulation of kappa opioid receptor-expressing ventral tegmental area neurons projecting to the ventrolateral periaqueductal gray which, when activated, selectively relieved opioid withdrawal-associated gastrointestinal distress. These discoveries highlight a critical role for midbrain kappa opioid receptor-expressing neurons and the downstream ventrolateral periaqueductal gray in opioid withdrawal-associated disruption of hedonic homeostasis and gastrointestinal regulation.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"7 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146033218","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}
Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.
{"title":"Ultrasound-assisted gene therapy mitigates Leigh syndrome pathology.","authors":"Mathilde Faideau,Romain Clément,Sébastien Rigollet,Giorgia Benegiamo,Cassandra Cresson,Béatrice Blot,Robin Reynaud-Dulaurier,Sara Yjjou,Fanny Aprahamian,Sylvère Durand,Anthony Delalande,Emmanuel L Barbier,Vasile Stupar,Johan Auwerx,Michael Decressac","doi":"10.1093/brain/awag026","DOIUrl":"https://doi.org/10.1093/brain/awag026","url":null,"abstract":"Leigh syndrome (LS) is a fatal neurometabolic disease caused by mutations in genes involved in mitochondrial energy harvesting. While there is currently no cure for this disease, pre-clinical studies showed that gene therapy can afford a therapeutic benefit in a relevant model of LS, the Ndufs4-KO mouse. However, similar results need to be obtained using methods that can be translated in patients. Here, we combined two tools that are approved for clinical interventions. We used low-intensity focused ultrasound (FUS) to transiently permeabilize the blood-brain barrier and thereby facilitate the passage of an AAV9 vector. This approach resulted in transgene expression in the brain and peripheral organs. When applied to one-month old Ndufs4-KO mice, this gene replacement strategy significantly extended the survival of the animals and ameliorated brain and cardiac function. These improvements were associated with the restoration of protein expression and mitochondrial function. These findings support the potential of combining FUS with AAV-mediated gene delivery to treat LS and they warrant further clinical translation. This study also provides the first evidence that ultrasound-assisted gene replacement can exert a therapeutic effect in a condition affecting the central nervous system.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"51 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146021727","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}
Rupal I Mehta,Tianhao Wang,Sue E Leurgans,David A Bennett,Julie A Schneider
Cerebral amyloid angiopathy (CAA) is associated with age, apolipoprotein E (APOE) genotype, and a pathologic diagnosis of Alzheimer's disease (AD). Yet, the complete spectrum of CAA presence and severity across age, APOE genotype, AD and AD related disorders (ADRD) is incompletely reported. Additionally, recent experiments suggest associations of CAA with diffuse plaques. Here, we studied CAA in older adults who were followed in longitudinal studies of aging. Postmortem brains were evaluated for the presence and severity of CAA and co-pathologies. AD was defined as intermediate-to-high Alzheimer's disease neuropathologic change (ADNC). Regression models were used to analyze the association of AD-related (neuritic and diffuse plaques and neurofibrillary tangles) and ADRD-related counts with CAA, controlling for risk factors including demographics, AD, and APOE ε4. The 1938 participants with mean age-at-death of 89.8 years (SD=6.6) had no (415, 21.4%), mild (795, 41.0%), or moderate-to-severe (728, 37.6%) CAA. The odds of moderate-to-severe CAA was higher in persons who were older (odds ratio (OR) per 10 years older, 1.34, [95% CI, 1.22-1.63]), APOE ε4 allele carriers (OR, 3.62 [95% CI, 2.90-4.52]), or comorbid for AD (OR, 4.14 [95% CI, 3.28-5.23]). Despite strong association with AD, 117 of 1216 (9.62%) participants with AD had no CAA while 108 of 581 (18.59%) participants with moderate-to-severe CAA had no AD (i.e., none-to-low ADNC). However, moderate-to-severe CAA was associated with neuritic plaques (OR, 1.27 [95% CI, 1.09-1.48]) and neurofibrillary tangles (OR, 1.52 [95% CI, 1.32-1.76]). Among participants without AD, the odds of severe CAA was ∼28-fold higher in APOE Ɛ2 allele carriers when neuritic plaque and neurofibrillary tangle loads were higher. This unexpected association between CAA severity and combined neuritic plaque and neurofibrillary tangle load was not found in APOE Ɛ2 allele carriers when there was AD or in APOE Ɛ4 allele carriers with or without AD. ADRD were not related to CAA after controlling for AD and APOE Ɛ4. Logistic models using moderate-to-severe CAA as the outcome revealed an interaction between neurofibrillary tangles and neuritic plaques in the entire group (p=0.047) and in APOE Ɛ2 allele carriers (p=0.039). We conclude that CAA is associated with neuritic plaques and neurofibrillary tangles and this relationship is markedly enhanced in APOE ε2 allele carriers (exclude APOE Ɛ4) without AD. These findings indicate further work on the complex relationships between CAA and AD-related lesions must consider AD and APOE status for a more personalized approach to studying CAA.
{"title":"Cerebral amyloid angiopathy and Alzheimer's and related pathologies across APOE genotypes.","authors":"Rupal I Mehta,Tianhao Wang,Sue E Leurgans,David A Bennett,Julie A Schneider","doi":"10.1093/brain/awag025","DOIUrl":"https://doi.org/10.1093/brain/awag025","url":null,"abstract":"Cerebral amyloid angiopathy (CAA) is associated with age, apolipoprotein E (APOE) genotype, and a pathologic diagnosis of Alzheimer's disease (AD). Yet, the complete spectrum of CAA presence and severity across age, APOE genotype, AD and AD related disorders (ADRD) is incompletely reported. Additionally, recent experiments suggest associations of CAA with diffuse plaques. Here, we studied CAA in older adults who were followed in longitudinal studies of aging. Postmortem brains were evaluated for the presence and severity of CAA and co-pathologies. AD was defined as intermediate-to-high Alzheimer's disease neuropathologic change (ADNC). Regression models were used to analyze the association of AD-related (neuritic and diffuse plaques and neurofibrillary tangles) and ADRD-related counts with CAA, controlling for risk factors including demographics, AD, and APOE ε4. The 1938 participants with mean age-at-death of 89.8 years (SD=6.6) had no (415, 21.4%), mild (795, 41.0%), or moderate-to-severe (728, 37.6%) CAA. The odds of moderate-to-severe CAA was higher in persons who were older (odds ratio (OR) per 10 years older, 1.34, [95% CI, 1.22-1.63]), APOE ε4 allele carriers (OR, 3.62 [95% CI, 2.90-4.52]), or comorbid for AD (OR, 4.14 [95% CI, 3.28-5.23]). Despite strong association with AD, 117 of 1216 (9.62%) participants with AD had no CAA while 108 of 581 (18.59%) participants with moderate-to-severe CAA had no AD (i.e., none-to-low ADNC). However, moderate-to-severe CAA was associated with neuritic plaques (OR, 1.27 [95% CI, 1.09-1.48]) and neurofibrillary tangles (OR, 1.52 [95% CI, 1.32-1.76]). Among participants without AD, the odds of severe CAA was ∼28-fold higher in APOE Ɛ2 allele carriers when neuritic plaque and neurofibrillary tangle loads were higher. This unexpected association between CAA severity and combined neuritic plaque and neurofibrillary tangle load was not found in APOE Ɛ2 allele carriers when there was AD or in APOE Ɛ4 allele carriers with or without AD. ADRD were not related to CAA after controlling for AD and APOE Ɛ4. Logistic models using moderate-to-severe CAA as the outcome revealed an interaction between neurofibrillary tangles and neuritic plaques in the entire group (p=0.047) and in APOE Ɛ2 allele carriers (p=0.039). We conclude that CAA is associated with neuritic plaques and neurofibrillary tangles and this relationship is markedly enhanced in APOE ε2 allele carriers (exclude APOE Ɛ4) without AD. These findings indicate further work on the complex relationships between CAA and AD-related lesions must consider AD and APOE status for a more personalized approach to studying CAA.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"382 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015270","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}
Natalya Benina,Luna Buitrago,Francesca I De Simone,Rachel R Radwan,M Craig Miller,Katie Martin,Diana Dickson,Sara Ho,Abhay Moghekar,Marilyn Albert,Niklas Mattsson-Carlgren,Sebastian Palmqvist,Rik Ossenkoppele,Magnus Förnvik Jonsson,Oskar Hansson,Erik Stomrud,Pallavi Sachdev,Hongmei Niu,David Verbel,Douglas M Hawkins
Blood biomarkers have the potential to revolutionize Alzheimer's disease (AD) diagnosis, offering advantages over cerebrospinal fluid (CSF) and positron emission tomography (PET) due to their accessibility, scalability, and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1-42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from two hundred eight (208) participants (including 7 with Subjective Cognitive Decline, 150 with Mild Cognitive Impairment, 12 with Alzheimer's disease dementia, and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD, and MissionAD) were analyzed to measure Aβ 1-42, Aβ 1-40, and pTau 217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau 217 (p < 0.001) and plasma Aβ 1-42 (p = 0.0056) demonstrated significant discriminative power, whereas Aβ 1-40 (p = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau 217/Aβ 1-42 ratio, demonstrated enhanced classification performance (p < 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau 217/Aβ 1-42 ratio achieved a PPV of 94.44% and NPV of 94.28%, in the parametric model, comparable to plasma pTau 217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% vs. 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau 217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% vs. 35.1%). The plasma pTau 217/Aβ 1-42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau 217 alone. These findings support the evaluation of the clinical utility of the plasma pTau 217/Aβ 1-42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.
{"title":"Plasma pTau 217:β-amyloid 1-42 ratio for enhanced accuracy and reduced uncertainty in detecting amyloid pathology.","authors":"Natalya Benina,Luna Buitrago,Francesca I De Simone,Rachel R Radwan,M Craig Miller,Katie Martin,Diana Dickson,Sara Ho,Abhay Moghekar,Marilyn Albert,Niklas Mattsson-Carlgren,Sebastian Palmqvist,Rik Ossenkoppele,Magnus Förnvik Jonsson,Oskar Hansson,Erik Stomrud,Pallavi Sachdev,Hongmei Niu,David Verbel,Douglas M Hawkins","doi":"10.1093/brain/awag001","DOIUrl":"https://doi.org/10.1093/brain/awag001","url":null,"abstract":"Blood biomarkers have the potential to revolutionize Alzheimer's disease (AD) diagnosis, offering advantages over cerebrospinal fluid (CSF) and positron emission tomography (PET) due to their accessibility, scalability, and cost-effectiveness. This study evaluated the effectiveness of individual plasma biomarkers, such as phosphorylated Tau (pTau) 217, as well as biomarker combinations, with a focus on the pTau 217/β-Amyloid (Aβ) 1-42 ratio to predict amyloid positivity. To improve clinical utility, a dual threshold approach was applied to maximize predictive values and positive likelihood ratios while minimizing the proportion of indeterminate results. Plasma samples from two hundred eight (208) participants (including 7 with Subjective Cognitive Decline, 150 with Mild Cognitive Impairment, 12 with Alzheimer's disease dementia, and 39 with other cognitive conditions) from three cohorts (BioFINDER2, BIOCARD, and MissionAD) were analyzed to measure Aβ 1-42, Aβ 1-40, and pTau 217 levels using the Fujirebio LUMIPULSE® G1200 platform. Amyloid status was determined by FDA-cleared PET imaging and/or CSF biomarker ratios. Logistic regression modelling evaluated biomarkers either individually or in combination to identify those that best distinguished amyloid positivity. Clinically applicable thresholds were established through likelihood ratio analysis and further evaluated based on predictive values. When assessing the ability of individual plasma biomarkers to differentiate between amyloid-positive and amyloid-negative participants, plasma pTau 217 (p < 0.001) and plasma Aβ 1-42 (p = 0.0056) demonstrated significant discriminative power, whereas Aβ 1-40 (p = 0.30) did not. Notably, the integration of these biomarkers into the plasma pTau 217/Aβ 1-42 ratio, demonstrated enhanced classification performance (p < 0.001). Using a two-threshold approach based on positive and negative likelihood ratios (PLR/NLR) targets of 14/20, respectively, the plasma pTau 217/Aβ 1-42 ratio achieved a PPV of 94.44% and NPV of 94.28%, in the parametric model, comparable to plasma pTau 217 alone (PPV: 94.44%, NPV: 94.28%), but yielded fewer indeterminate results (26.5% vs. 38.6%). Using a non-parametric model, the plasma ratio achieved a PPV and NPV of 94.62% and 91.78%, respectively, while plasma pTau 217 alone achieved 92.41% and 92.86%; the ratio once again reduced the proportion of indeterminate results (20.2% vs. 35.1%). The plasma pTau 217/Aβ 1-42 ratio demonstrated superior performance in identifying amyloid pathology and reduced the frequency of indeterminate results compared to plasma pTau 217 alone. These findings support the evaluation of the clinical utility of the plasma pTau 217/Aβ 1-42 ratio as a tool for identifying amyloid pathology in patients presenting with cognitive complaints.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"99 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005578","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}
Ischaemic stroke is one of the leading causes of disability and death worldwide, yet effective treatment options remain limited. Bilateral hemisphere theta burst stimulation (TBS), a non-invasive brain stimulation technique, has shown considerable therapeutic potential in stroke. However, relevant research is still limited, and their specific mechanisms remain unclear. This study utilized a middle cerebral artery occlusion (MCAO) model in non-human primates to explore the application of bilateral hemispheric TBS in stroke rehabilitation. By integrating behavioural assessments, electrophysiology, fMRI, DTI, and proteomics, the study evaluated the effects of TBS on neural repair, functional recovery, and brain region remodeling. TBS significantly improved upper limb function after MCAO, regulated cortical excitability imbalance, enhanced neural conduction efficiency, and showed notable improvements in functional connectivity and white matter repair across multiple brain regions. Proteomic analysis further revealed the potential roles of TBS in neurorepair, metabolic regulation, and anti-inflammatory effects. Additionally, large-scale genetic analysis indicated that ischaemic stroke may alter white matter structure by affecting blood proteins, and TBS intervention may help reverse these blood protein changes, thereby promoting white matter repair. These findings provide new insights for optimizing stroke treatment strategies. TBS promotes functional recovery by enhancing neuroplasticity.
{"title":"Bilateral theta burst stimulation aids neural repair and recovery after ischaemic stroke in primates.","authors":"Gengbin Chen,Manfeng Wu,Ge Li,Zhongqiang Huang,Yunfeng Li,Yalun Guan,Yuanhuan Ma,Tuo Lin,Jialin Chen,Yinchun Zhao,Qixing Hu,Cheng Wu,Jianping Lv,Yu Zhang,Guangqing Xu,Yue Lan","doi":"10.1093/brain/awag022","DOIUrl":"https://doi.org/10.1093/brain/awag022","url":null,"abstract":"Ischaemic stroke is one of the leading causes of disability and death worldwide, yet effective treatment options remain limited. Bilateral hemisphere theta burst stimulation (TBS), a non-invasive brain stimulation technique, has shown considerable therapeutic potential in stroke. However, relevant research is still limited, and their specific mechanisms remain unclear. This study utilized a middle cerebral artery occlusion (MCAO) model in non-human primates to explore the application of bilateral hemispheric TBS in stroke rehabilitation. By integrating behavioural assessments, electrophysiology, fMRI, DTI, and proteomics, the study evaluated the effects of TBS on neural repair, functional recovery, and brain region remodeling. TBS significantly improved upper limb function after MCAO, regulated cortical excitability imbalance, enhanced neural conduction efficiency, and showed notable improvements in functional connectivity and white matter repair across multiple brain regions. Proteomic analysis further revealed the potential roles of TBS in neurorepair, metabolic regulation, and anti-inflammatory effects. Additionally, large-scale genetic analysis indicated that ischaemic stroke may alter white matter structure by affecting blood proteins, and TBS intervention may help reverse these blood protein changes, thereby promoting white matter repair. These findings provide new insights for optimizing stroke treatment strategies. TBS promotes functional recovery by enhancing neuroplasticity.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"277 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015266","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}
Psychiatric symptoms are very common in Huntington's disease (HD). In keeping with other neurodegenerative diseases, there are concerns that antidepressants may worsen disease progression. Previous work on antidepressant effects in HD has been limited by confounding by indication, small sample sizes, short follow-up or a combination of these. We leveraged data from the ENROLL-HD (25550 participants) cohort to determine if 1) symptoms associated with antidepressant initiation are associated with faster disease progression and 2) antidepressants have an impact on disease progression and mortality in people with HD (pwHD) experiencing these symptoms. We first determined the commonest indications for antidepressant prescription in pwHD. We selected adult pwHD (age ≥18, genetically confirmed HD), not on antidepressants and free of antidepressant-indication symptoms at baseline, (N=6166) and used linear mixed models to determine the association between symptoms listed as indications for antidepressant prescription and disease progression and mortality. Using propensity score weighting, we selected adult pwHD who remained antidepressant-naive until an episode of antidepressant-indication symptoms (N=1877) and compared disease progression and mortality between those starting an antidepressant (N=194) before the next follow-up versus those who did not (N=1683). Outcomes were 1) disease progression measured by the composite disease score in ENROLL-HD; and 2) mortality. Depression and anxiety accounted for >80% of indications for antidepressant prescription in pwHD: episodes of depression/anxiety (experienced by 3131/6166) were associated with increased composite disease score progression from 0.46 to 0.52/year (p=3.1x10-11), and increased mortality (Hazard Ratio=1.5,p=9.4x10-6). In pwHD with new depression/anxiety free of antidepressants at symptom onset, antidepressant initiation (N=194/1877) 1) reduced composite disease score decline from 0.89 to 0.53/year (p=0.002); and 2) reduced all cause mortality(Hazard Ratio 0.38,p=0.04). An exploratory analysis of antidepressant classes showed that TCAs reduced suicide and non-suicide mortality; SSRIs and atypical agents reduced suicide risk, whilst SNRIs reduced non-suicide related mortality. Depression and anxiety are associated with more rapid disease progression and increased mortality in HD. In pwHD affected by depression and anxiety, antidepressant initiation slows disease progression and reduces mortality risk, with preliminary evidence of antidepressant-class specific reduction in both suicide and non-suicide mortality risk. This finding warrants further investigation in both HD and other neurodegenerative diseases.
{"title":"Exploring the association between antidepressants, progression and mortality in Huntington's disease.","authors":"Duncan Mclauchlan,Cheney Drew,Peter Holmans,Anne Rosser","doi":"10.1093/brain/awag009","DOIUrl":"https://doi.org/10.1093/brain/awag009","url":null,"abstract":"Psychiatric symptoms are very common in Huntington's disease (HD). In keeping with other neurodegenerative diseases, there are concerns that antidepressants may worsen disease progression. Previous work on antidepressant effects in HD has been limited by confounding by indication, small sample sizes, short follow-up or a combination of these. We leveraged data from the ENROLL-HD (25550 participants) cohort to determine if 1) symptoms associated with antidepressant initiation are associated with faster disease progression and 2) antidepressants have an impact on disease progression and mortality in people with HD (pwHD) experiencing these symptoms. We first determined the commonest indications for antidepressant prescription in pwHD. We selected adult pwHD (age ≥18, genetically confirmed HD), not on antidepressants and free of antidepressant-indication symptoms at baseline, (N=6166) and used linear mixed models to determine the association between symptoms listed as indications for antidepressant prescription and disease progression and mortality. Using propensity score weighting, we selected adult pwHD who remained antidepressant-naive until an episode of antidepressant-indication symptoms (N=1877) and compared disease progression and mortality between those starting an antidepressant (N=194) before the next follow-up versus those who did not (N=1683). Outcomes were 1) disease progression measured by the composite disease score in ENROLL-HD; and 2) mortality. Depression and anxiety accounted for >80% of indications for antidepressant prescription in pwHD: episodes of depression/anxiety (experienced by 3131/6166) were associated with increased composite disease score progression from 0.46 to 0.52/year (p=3.1x10-11), and increased mortality (Hazard Ratio=1.5,p=9.4x10-6). In pwHD with new depression/anxiety free of antidepressants at symptom onset, antidepressant initiation (N=194/1877) 1) reduced composite disease score decline from 0.89 to 0.53/year (p=0.002); and 2) reduced all cause mortality(Hazard Ratio 0.38,p=0.04). An exploratory analysis of antidepressant classes showed that TCAs reduced suicide and non-suicide mortality; SSRIs and atypical agents reduced suicide risk, whilst SNRIs reduced non-suicide related mortality. Depression and anxiety are associated with more rapid disease progression and increased mortality in HD. In pwHD affected by depression and anxiety, antidepressant initiation slows disease progression and reduces mortality risk, with preliminary evidence of antidepressant-class specific reduction in both suicide and non-suicide mortality risk. This finding warrants further investigation in both HD and other neurodegenerative diseases.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"64 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146015267","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}
Alberto Averna,Mario Sousa,Elena Bernasconi,Eduardo Moraud,Claudio Pollo,Paul Krack,Hagai Bergman,Benoit Duchet,Gerd Tinkhauser
Movement-related gamma activity (>60 Hz) in cortico-basal ganglia networks reflects pro-kinetic synchronisation dynamics. While in the cortex these temporal dynamics are known to unfold spatially across topographically distributed networks, it remains unclear whether a similar spatial propagation occurs within the basal ganglia, and how such spatial encoding may contribute to both physiological and disease-related mechanisms. The subthalamic nucleus (STN) is a key integrative hub for motor processing within the basal ganglia-cortical circuitry. At rest, STN activity is topographically distributed according to its spectral frequency components. To assess whether this spectral topography is dynamic and underlies movement encoding, we dissected the spatiotemporal properties of STN local field potentials recorded intraoperatively at rest and during movement across 63 hemispheres from patients with Parkinson's disease (PD). Using multi-contact deep brain stimulation leads, we captured high-resolution anatomical signal dynamics and contrasted a broad frequency spectrum (60-400 Hz), including high-gamma, fast-gamma, slow high-frequency oscillations, and fast high-frequency oscillations. Moreover, we compared these signals to upper limb muscle activity and movement-related beta desynchronisation, and examined their association to clinical impairment and levodopa responsiveness. All sub-bands exhibited significant movement-related synchronisation in both the contralateral and ipsilateral STN, however with distinct magnitude and temporal dynamics. Presence and degree of temporal locking to muscle activity and inverse relationship to movement-related beta desynchronisation also varied by sub-band. Importantly, each sub-band exhibited spatially-segregated hotspots located within the STN that propagate primarily along the inferior-superior axis, yet in band-specific directions. This spatial propagation evolved throughout the movement period but temporally decoupled from synchronization magnitude, indicating that spatial dynamics reflect a distinct property relevant for motor encoding. Notably, propagation of frequencies above 110 Hz inversely correlated with dopamine-related motor improvement, suggesting that exaggerated spatial dynamics may reflect compensatory mechanisms secondary to neurodegeneration. These findings demonstrated that synchronisation within the basal ganglia is not a spatially static phenomenon but rather unfolds in space which expands on the current understanding of basal ganglia mechanism. High-frequency propagation may serve as a potential marker for motor impairment in PD, opening new avenues for spectro-behavioral research and spatially-informed neuromodulation strategies.
{"title":"Spatial propagation of movement-related basal ganglia activity predicts parkinsonian motor state.","authors":"Alberto Averna,Mario Sousa,Elena Bernasconi,Eduardo Moraud,Claudio Pollo,Paul Krack,Hagai Bergman,Benoit Duchet,Gerd Tinkhauser","doi":"10.1093/brain/awag019","DOIUrl":"https://doi.org/10.1093/brain/awag019","url":null,"abstract":"Movement-related gamma activity (>60 Hz) in cortico-basal ganglia networks reflects pro-kinetic synchronisation dynamics. While in the cortex these temporal dynamics are known to unfold spatially across topographically distributed networks, it remains unclear whether a similar spatial propagation occurs within the basal ganglia, and how such spatial encoding may contribute to both physiological and disease-related mechanisms. The subthalamic nucleus (STN) is a key integrative hub for motor processing within the basal ganglia-cortical circuitry. At rest, STN activity is topographically distributed according to its spectral frequency components. To assess whether this spectral topography is dynamic and underlies movement encoding, we dissected the spatiotemporal properties of STN local field potentials recorded intraoperatively at rest and during movement across 63 hemispheres from patients with Parkinson's disease (PD). Using multi-contact deep brain stimulation leads, we captured high-resolution anatomical signal dynamics and contrasted a broad frequency spectrum (60-400 Hz), including high-gamma, fast-gamma, slow high-frequency oscillations, and fast high-frequency oscillations. Moreover, we compared these signals to upper limb muscle activity and movement-related beta desynchronisation, and examined their association to clinical impairment and levodopa responsiveness. All sub-bands exhibited significant movement-related synchronisation in both the contralateral and ipsilateral STN, however with distinct magnitude and temporal dynamics. Presence and degree of temporal locking to muscle activity and inverse relationship to movement-related beta desynchronisation also varied by sub-band. Importantly, each sub-band exhibited spatially-segregated hotspots located within the STN that propagate primarily along the inferior-superior axis, yet in band-specific directions. This spatial propagation evolved throughout the movement period but temporally decoupled from synchronization magnitude, indicating that spatial dynamics reflect a distinct property relevant for motor encoding. Notably, propagation of frequencies above 110 Hz inversely correlated with dopamine-related motor improvement, suggesting that exaggerated spatial dynamics may reflect compensatory mechanisms secondary to neurodegeneration. These findings demonstrated that synchronisation within the basal ganglia is not a spatially static phenomenon but rather unfolds in space which expands on the current understanding of basal ganglia mechanism. High-frequency propagation may serve as a potential marker for motor impairment in PD, opening new avenues for spectro-behavioral research and spatially-informed neuromodulation strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"39 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005414","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}
Lydia Trudel,Joseph Therriault,Arthur C Macedo,Seyyed A Hosseini,Jaime Fernandez-Arias,Tevy Chan,Nesrine Rahmouni,Gleb Bezgin,Cécile Tissot,Marcel S Woo,Étienne Aumont,Yansheng Zheng,Brandon Hall,Delphine Oliva-Lopez,Stuart W Mitchell,Robert Hopewell,Chris Hung-Hsin Hsiao,Arthur W Toga,Meredith N Braskie,Karin L Meeker,Jean-Paul Soucy,Marie-Christine Guiot,Serge Gauthier,Paolo Vitali,Sid E O'Bryant,Tharick A Pascoal,Pedro Rosa-Neto
Alzheimer's disease (AD) is defined by its characteristic neuropathologic changes, which allow for diagnosis and assessment of severity. Recently, the Alzheimer's Association proposed a framework to stage Alzheimer's disease biologically based on tau-PET. Furthermore, the framework hypothesizes a degree of alignment between biological Alzheimer's disease severity and clinical symptom severity. We aimed to investigate the concordance between clinical and biological stages of Alzheimer's disease and explore factors contributing to discordance using in vivo and postmortem neuropathological data. Data from 768 amyloid-β positive individuals were drawn from four observational cross-sectional in vivo cohorts-TRIAD, ADNI, HABS-HD, and SCAN-as well as a postmortem autopsy dataset from the National Alzheimer's Coordinating Center (NACC; n = 3,188). All in vivo participants had tau-PET imaging, clinical diagnosis, and neurobehavioral assessments. Participants were assigned a biological Alzheimer's disease stage based on their tau-PET scan according to the Alzheimer's Association revised criteria stages. The autopsy dataset included individuals with moderate-to-frequent neuritic plaques (CERAD scores 2-3), along with premortem clinical and neurobehavioral data. Clinical-biological concordance was quantified using squared-weighted Cohen's Kappa. Ordinal and linear regression models assessed associations between biological stage and clinical severity (CDR-Sum of Boxes, MMSE), adjusting for age, sex, and cohort. Postmortem analyses evaluated the impact of comorbid neuropathologies on clinical-biological discordance using adjusted odds ratios and ordinal regression. Overall concordance between clinical and biological Alzheimer's disease staging was moderate (Cohen's Kappa=0.52, p < 0.001). Approximately 70% of individuals classified as cognitively unimpaired or with dementia exhibited biological stages consistent with their clinical diagnoses. In contrast, transitional decline and mild cognitive impairment (MCI) groups were more heterogenous. Notably, 25% of Aβ-positive individuals with MCI demonstrated no detectable tau-PET abnormality. Nonetheless, advanced tau-PET stage was reliably associated with clinical impairment. In the NACC autopsy dataset, nearly all individuals with more severe clinical stage than their proposed biological stage exhibited comorbid neuropathologies, including FTLD-TDP-43, FTLD-tau, Lewy bodies, LATE, and cerebrovascular disease. The number of comorbid pathologies was strongly associated with increased odds of clinical dementia (t = 8.45, p < 0.001). While there is moderate agreement between clinical and biological stages of Alzheimer's disease across the entire disease spectrum, strong agreement is found in clinically unimpaired and dementia stages. Comparison of clinical and biological Alzheimer's disease stages provides a framework for understanding the large contributions of non-AD neurodegenerative diseases to dementia in Aβ-posi
阿尔茨海默病（AD）的定义是其特征性的神经病理变化，允许诊断和评估严重程度。最近，阿尔茨海默病协会提出了一个基于tau-PET的阿尔茨海默病生物学分期框架。此外，该框架假设阿尔茨海默病的生物学严重程度和临床症状严重程度之间存在一定程度的一致性。我们的目的是研究阿尔茨海默病的临床和生物学阶段之间的一致性，并利用体内和死后的神经病理学数据探讨导致不一致性的因素。来自768个淀粉样蛋白-β阳性个体的数据来自四个观察性横断面体内队列- triad， ADNI， HABS-HD和扫描-以及来自国家阿尔茨海默病协调中心（NACC; n = 3188）的尸检数据集。所有体内参与者都进行了tau-PET成像、临床诊断和神经行为评估。根据阿尔茨海默病协会修订的标准阶段，参与者根据他们的tau-PET扫描被分配一个生物学阿尔茨海默病阶段。尸检数据集包括中度至频繁神经斑块（CERAD评分2-3）的个体，以及死前临床和神经行为数据。临床-生物学一致性采用平方加权Cohen’s Kappa进行量化。顺序和线性回归模型评估了生物学分期和临床严重程度（CDR-Sum of Boxes， MMSE）之间的关系，并对年龄、性别和队列进行了调整。采用校正优势比和有序回归，对共病神经病理对临床生物学不一致的影响进行尸检分析。阿尔茨海默病临床分期与生物学分期的总体一致性为中等（Cohen’s Kappa=0.52, p < 0.001）。大约70%被归类为认知未受损或患有痴呆症的个体表现出与其临床诊断一致的生物学阶段。相比之下，过渡性衰退和轻度认知障碍（MCI）组更具异质性。值得注意的是，25%的a β阳性MCI患者没有检测到tau-PET异常。尽管如此，晚期tau-PET阶段与临床损害可靠相关。在NACC尸检数据集中，几乎所有临床分期比其提出的生物学分期更严重的个体都表现出共病性神经病变，包括FTLD-TDP-43、FTLD-tau、路易小体、LATE和脑血管疾病。共病病理的数量与临床痴呆的几率增加密切相关（t = 8.45, p < 0.001）。在整个疾病谱系中，阿尔茨海默病的临床阶段和生物学阶段之间存在适度的一致性，但在临床未受损阶段和痴呆阶段发现了强烈的一致性。阿尔茨海默病临床和生物学分期的比较为理解非ad神经退行性疾病对a β阳性个体痴呆的巨大贡献提供了一个框架。我们的研究结果对临床试验招募策略具有重要意义，并强调了对非阿尔茨海默病病理过程生物标志物的迫切需求。
{"title":"Clinical-biological Alzheimer's disease stage concordance: insights from cohorts and autopsy data.","authors":"Lydia Trudel,Joseph Therriault,Arthur C Macedo,Seyyed A Hosseini,Jaime Fernandez-Arias,Tevy Chan,Nesrine Rahmouni,Gleb Bezgin,Cécile Tissot,Marcel S Woo,Étienne Aumont,Yansheng Zheng,Brandon Hall,Delphine Oliva-Lopez,Stuart W Mitchell,Robert Hopewell,Chris Hung-Hsin Hsiao,Arthur W Toga,Meredith N Braskie,Karin L Meeker,Jean-Paul Soucy,Marie-Christine Guiot,Serge Gauthier,Paolo Vitali,Sid E O'Bryant,Tharick A Pascoal,Pedro Rosa-Neto","doi":"10.1093/brain/awag018","DOIUrl":"https://doi.org/10.1093/brain/awag018","url":null,"abstract":"Alzheimer's disease (AD) is defined by its characteristic neuropathologic changes, which allow for diagnosis and assessment of severity. Recently, the Alzheimer's Association proposed a framework to stage Alzheimer's disease biologically based on tau-PET. Furthermore, the framework hypothesizes a degree of alignment between biological Alzheimer's disease severity and clinical symptom severity. We aimed to investigate the concordance between clinical and biological stages of Alzheimer's disease and explore factors contributing to discordance using in vivo and postmortem neuropathological data. Data from 768 amyloid-β positive individuals were drawn from four observational cross-sectional in vivo cohorts-TRIAD, ADNI, HABS-HD, and SCAN-as well as a postmortem autopsy dataset from the National Alzheimer's Coordinating Center (NACC; n = 3,188). All in vivo participants had tau-PET imaging, clinical diagnosis, and neurobehavioral assessments. Participants were assigned a biological Alzheimer's disease stage based on their tau-PET scan according to the Alzheimer's Association revised criteria stages. The autopsy dataset included individuals with moderate-to-frequent neuritic plaques (CERAD scores 2-3), along with premortem clinical and neurobehavioral data. Clinical-biological concordance was quantified using squared-weighted Cohen's Kappa. Ordinal and linear regression models assessed associations between biological stage and clinical severity (CDR-Sum of Boxes, MMSE), adjusting for age, sex, and cohort. Postmortem analyses evaluated the impact of comorbid neuropathologies on clinical-biological discordance using adjusted odds ratios and ordinal regression. Overall concordance between clinical and biological Alzheimer's disease staging was moderate (Cohen's Kappa=0.52, p < 0.001). Approximately 70% of individuals classified as cognitively unimpaired or with dementia exhibited biological stages consistent with their clinical diagnoses. In contrast, transitional decline and mild cognitive impairment (MCI) groups were more heterogenous. Notably, 25% of Aβ-positive individuals with MCI demonstrated no detectable tau-PET abnormality. Nonetheless, advanced tau-PET stage was reliably associated with clinical impairment. In the NACC autopsy dataset, nearly all individuals with more severe clinical stage than their proposed biological stage exhibited comorbid neuropathologies, including FTLD-TDP-43, FTLD-tau, Lewy bodies, LATE, and cerebrovascular disease. The number of comorbid pathologies was strongly associated with increased odds of clinical dementia (t = 8.45, p < 0.001). While there is moderate agreement between clinical and biological stages of Alzheimer's disease across the entire disease spectrum, strong agreement is found in clinically unimpaired and dementia stages. Comparison of clinical and biological Alzheimer's disease stages provides a framework for understanding the large contributions of non-AD neurodegenerative diseases to dementia in Aβ-posi","PeriodicalId":9063,"journal":{"name":"Brain","volume":"11 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146005416","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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