JAMA neurology最新文献

Importance: Anti-β-amyloid immunotherapy using lecanemab is becoming increasingly available to patients with Alzheimer disease (AD). Individuals with Down syndrome (DS) develop AD neuropathology by age 40 years, representing a significant cohort of genetically determined AD.

Objective: To investigate the binding properties of lecanemab in the brains of people with DS, in anticipation of their inclusion in clinical trials or access to antiamyloid immunotherapies.

Design, setting, participants: The study included cases of postmortem brain tissue analysis from 15 individuals with DS aged 43 to 68 years that were acquired from Alzheimer Disease research centers at the University of California, Irvine and the University of Kentucky from 2008 to 2021. Data were analyzed from August 2023 through May 2024.

Exposure: The binding properties of lecanemab were assessed in brain tissue.

Main outcome: The primary outcome was the extent of lecanemab binding to amyloid plaques and brain blood vessels.

Results: Tissue from 15 people (8 were female [53%]) with DS ranging in age from 43 to 68 (mean, 56.6) years were included in the study. Lecanemab-labeled amyloid plaques appeared in all 15 DS cases studied, indicating potential target engagement. However, extensive binding of lecanemab to brain blood vessels in DS was observed, raising significant safety concerns. These findings underscore the necessity for clinical trials of lecanemab in people with DS to evaluate both safety and efficacy, particularly in individuals older than 43 years.

Conclusions and relevance: These findings suggest significant binding of lecanemab to cerebral amyloid angiopathy in DS. Lecanemab should be rigorously tested in clinical trials for AD in the DS population to determine its safety and efficacy, especially in those older than 43 years.

Importance: The X chromosome has remained enigmatic in Alzheimer disease (AD), yet it makes up 5% of the genome and carries a high proportion of genes expressed in the brain, making it particularly appealing as a potential source of unexplored genetic variation in AD.

Objectives: To perform the first large-scale X chromosome-wide association study (XWAS) of AD.

Design, setting, and participants: This was a meta-analysis of genetic association studies in case-control, family-based, population-based, and longitudinal AD-related cohorts from the US Alzheimer's Disease Genetics Consortium, the Alzheimer's Disease Sequencing Project, the UK Biobank, the Finnish health registry, and the US Million Veterans Program. Risk of AD was evaluated through case-control logistic regression analyses. Data were analyzed between January 2023 and March 2024. Genetic data available from high-density single-nucleotide variant microarrays and whole-genome sequencing and summary statistics for multitissue expression and protein quantitative trait loci available from published studies were included, enabling follow-up genetic colocalization analyses. A total of 1 629 863 eligible participants were selected from referred and volunteer samples, 477 596 of whom were excluded for analysis exclusion criteria. The number of participants who declined to participate in original studies was not available.

Main outcome and measures: Risk of AD, reported as odds ratios (ORs) with 95% CIs. Associations were considered at X chromosome-wide (P < 1 × 10-5) and genome-wide (P < 5 × 10-8) significance. Primary analyses are nonstratified, while secondary analyses evaluate sex-stratified effects.

Results: Analyses included 1 152 284 participants of non-Hispanic White, European ancestry (664 403 [57.7%] female and 487 881 [42.3%] male), including 138 558 individuals with AD. Six independent genetic loci passed X chromosome-wide significance, with 4 showing support for links between the genetic signal for AD and expression of nearby genes in brain and nonbrain tissues. One of these 4 loci passed conservative genome-wide significance, with its lead variant centered on an intron of SLC9A7 (OR, 1.03; 95% CI, 1.02-1.04) and colocalization analyses prioritizing both the SLC9A7 and nearby CHST7 genes. Of these 6 loci, 4 displayed evidence for escape from X chromosome inactivation with regard to AD risk.

Conclusion and relevance: This large-scale XWAS of AD identified the novel SLC9A7 locus. SLC9A7 regulates pH homeostasis in Golgi secretory compartments and is anticipated to have downstream effects on amyloid β accumulation. Overall, this study advances our knowledge of AD genetics and may provide novel biological drug targets. The results further provide initial insights into elucidating the role of the X chromosome in sex-based differences in AD.

Importance: In several randomized clinical trials, endovascular thrombectomy led to better functional outcomes than conventional treatment at 90 days poststroke in patients with acute basilar artery occlusion. However, the long-term clinical outcomes of these patients have not been well delineated.

Objective: To evaluate 1-year clinical outcomes in patients with acute basilar artery occlusion following endovascular thrombectomy vs control.

Design, setting, and participants: This study is an extension of the ATTENTION trial, a multicenter, randomized clinical trial. Patients were included between February 2021 and January 2022, with 1-year follow-up through April 2023. This multicenter, population-based study was conducted at 36 comprehensive stroke sites. Patients with acute basilar artery occlusion within 12 hours of estimated symptom onset were included. Of the 342 patients randomized in the ATTENTION trial, 330 (96.5%) had 1-year follow-up information available.

Exposures: Endovascular thrombectomy (thrombectomy group) vs best medical treatment (control group).

Main outcomes and measures: The primary outcome was defined as a score of 0 to 3 on the modified Rankin Scale (mRS) at 1 year. Secondary outcomes were functional independence (mRS score 0-2), excellent outcome (mRS score 0-1), level of disability (distribution of all 7 mRS scores), mortality, and health-related quality of life at 1 year.

Results: Among 330 patients who had 1-year follow-up data, 227 (68.8%) were male, and the mean (SD) age was 67.0 (10.7) years. An mRS score 0 to 3 at 1 year was achieved by 99 of 222 patients (44.6%) in the thrombectomy group and 21 of 108 (19.4%) in the control group (adjusted rate ratio, 2.23; 95% CI, 1.51-3.29). Mortality at 1 year compared with 90 days was more frequent in both the thrombectomy group (101 of 222 [45.5%] vs 83 of 226 [36.7%]) and the control group (69 of 108 [63.9%] vs 63 of 114 [55.3%]). Excellent outcome (mRS score 0-1) at 1 year compared with 90 days increased in the thrombectomy group (62 of 222 [27.9%] vs 45 of 226 [19.9%]) but not in the control group (9 of 108 [8.3%] vs 9 of 114 [7.9%]) resulting in a magnified treatment benefit.

Conclusions and relevance: Among patients with basilar artery occlusion within 12 hours of onset, the benefits of endovascular thrombectomy at 1 year compared with 90 days were sustained for favorable (mRS score 0-3) outcome and enhanced for excellent (mRS score 0-1) outcome.