Aikaterini Smaragdi Papadopoulou, Christian Landles, Edward J Smith, Marie K Bondulich, Annett Boeddrich, Maria Canibano-Pico, Emily C E Danby, Franziska Hoschek, Arzo Iqbal, Samuel T Jones, Nancy Neuendorf, Iulia M Nita, Georgina F Osborne, Jemima Phillips, Maximilian Wagner, Erich E Wanker, Jonathan R Greene, Andreas Neueder, Gillian P Bates
The mutation that causes Huntington’s disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington’s disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies.
{"title":"The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington’s disease","authors":"Aikaterini Smaragdi Papadopoulou, Christian Landles, Edward J Smith, Marie K Bondulich, Annett Boeddrich, Maria Canibano-Pico, Emily C E Danby, Franziska Hoschek, Arzo Iqbal, Samuel T Jones, Nancy Neuendorf, Iulia M Nita, Georgina F Osborne, Jemima Phillips, Maximilian Wagner, Erich E Wanker, Jonathan R Greene, Andreas Neueder, Gillian P Bates","doi":"10.1093/brain/awag040","DOIUrl":"https://doi.org/10.1093/brain/awag040","url":null,"abstract":"The mutation that causes Huntington’s disease is a CAG repeat expansion in exon 1 of the huntingtin gene (HTT) that leads to an abnormally long polyglutamine tract in the huntingtin protein (HTT). Mutant CAG repeats are unstable and increase in size in specific neurons and brain regions with age, a phenomenon that constitutes the first step in the pathogenesis of the disease. In the presence of an expanded CAG repeat, cryptic polyA sites in intron 1 of the HTT pre-mRNA can become activated leading to the polyadenylation of a prematurely terminated transcript, HTT1a. This encodes the HTT1a protein, which is known to be very aggregation-prone and highly pathogenic. Given that the longer the CAG repeat the more HTT1a is generated, could the production of HTT1a be the mechanism through which somatic CAG repeat expansion exerts its pathogenic consequences? Resolving this issue is very important for the design of therapeutic approaches to lower huntingtin levels. We have used a CRISPR-Cas9 approach to prevent the production of HTT1a in a knock-in mouse model of Huntington’s disease. All potential cryptic polyA sites were deleted from Htt intron 1 in HdhQ150 mice and colonies were established that were heterozygous for the intron 1 deletion on a mutant allele (HdhQ150ΔI) and heterozygous for the deletion on a wild-type allele (WTΔI). The CAG repeat sizes in the HdhQ150 and HdhQ150ΔI colonies were well-matched at approximately 195 CAGs. As predicted, the deletion of the cryptic polyA sites from Htt intron 1 prevented the generation of the Htt1a transcript in the HdhQ150ΔI mice. However, very low levels of the HTT1a protein were detected, which resulted from a Htt readthrough product of exon 1 and exon 2, that had retained the deleted intron and terminated at a cryptic polyA site in intron 2. HdhQ150, HdhQ150ΔI, wild-type and WTΔI mice were studied until 17 months of age. Immunohistochemical and homogeneous time resolved fluorescence analysis showed that HTT aggregation in both HdhQ150 and HdhQ150ΔI brains contained HTT1a, but the dramatic decrease in soluble HTT1a levels in HdhQ150ΔI brains delayed the appearance of aggregated HTT1a by several months. Although this delay in aggregate pathology only partially reversed transcriptional dysregulation, the biomarkers NEFL and BRP39 (YKL40) remained at wild-type levels in HdhQ150ΔI mice at 17 months of age. These data demonstrate that the production of HTT1a initiates HTT aggregation and that it is important to target HTT1a in huntingtin-lowering therapeutic strategies.","PeriodicalId":9063,"journal":{"name":"Brain","volume":"23 1","pages":""},"PeriodicalIF":14.5,"publicationDate":"2026-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146098263","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}
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}
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}
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}
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}
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