Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Cross-sectional associations between neighborhood characteristics, cognition and dementia risk factor burden in middle-aged and older Australians.

Dementia disproportionately affects individuals from disadvantaged backgrounds, including those living in areas of lower neighborhood-level socioeconomic status. It is important to understand whether there are specific neighborhood characteristics associated with dementia risk factors and cognition which may inform dementia risk reduction interventions. We sought to examine whether greenspace, walkability, and crime associated with the cumulative burden of modifiable dementia risk factors and cognition. This was a cross-sectional analysis of 2016-2020 data from the Healthy Brain Project, a population-based cohort of community-dwelling individuals across Australia. Participants were aged 40-70 and free of dementia. Measures included greenspace (greenspace % in the local area, and distance to greenspace, n = 2,181); and intersection density (n = 1,159), and crime (rate of recorded offences; n = 1,159). Outcomes included a modified Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score to index the burden of modifiable vascular dementia risk factors; and composite scores of both memory and attention, derived from the Cogstate Brief Battery. Linear regressions adjusted for age, sex, education, and personal socio-economic status, demonstrated distance to greenspace (b ± SE per 2-fold increase = 0.09 ± 0.03, p =.005) and crime rate (b ± SE per 2-fold increase = 0.07 ± 0.03, p =.018) were associated with higher modified CAIDE. Higher crime was associated with lower memory performance (b ± SE = -0.03 ± 0.01, p =.018). The association between distance to greenspace and modified CAIDE was only present in low-moderate socioeconomic status neighborhoods (p interaction = 0.004). Dementia prevention programs that address modifiable risk factors in midlife should consider the possible role of neighborhood characteristics.

Association of Time to Thrombolysis With Early Reperfusion After Alteplase and Tenecteplase in Patients With Large Vessel Occlusion.

BACKGROUND AND OBJECTIVES: Early treatment with intravenous alteplase increases the probability of lytic-induced reperfusion in large vessel occlusion (LVO) patients. The relationship of tenecteplase-induced reperfusion and the timing of thrombolytic administration has not been explored. In this study, we performed a comparative analysis of tenecteplase and alteplase reperfusion rates and assessed their relationship to the time of thrombolytic administration. METHODS: Patients who were initially treated with a thrombolytic within 4.5 hours of symptom onset were pooled from the Royal Melbourne Stroke Registry, EXTEND-IA, EXTEND-IA TNK, and EXTEND-IA TNK part 2 trials. The primary outcome, thrombolytic-induced reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion at initial angiographic assessment (or repeat CT perfusion/angiography). We compared the treatment effect of tenecteplase and alteplase through fixed-effects Poisson regression modelling. RESULTS: Among 846 patients included in the primary analysis, early reperfusion was observed in 173 (20%) patients (tenecteplase: 98/470 [21%], onset-to-thrombolytic time: 132 minutes [interquartile range (IQR): 99-170], and thrombolytic-to-assessment time: 61 minutes [IQR: 39-96]; alteplase: 75/376 [19%], onset-to-thrombolytic time: 143 minutes [IQR: 105-180], thrombolytic-to-assessment time: 92 minutes [IQR: 63-144]). Earlier onset-to-thrombolytic administration times were associated with an increased probability of thrombolytic-induced reperfusion in patients treated with either tenecteplase (adjusted risk ratio [aRR] 1.05 per 15 minutes [95% confidence interval (CI) 1.00-1.12] or alteplase (aRR 1.06 per 15 minutes [95% CI 1.00-1.13]). Tenecteplase remained associated with higher rates of reperfusion vs alteplase after adjustment for onset-to-thrombolytic time, occlusion site, thrombolytic-to-assessment time, and study as a fixed effect, (adjusted incidence rate ratio: 1.41 [95% CI 1.02-1.93]). No significant treatment-by-time interaction was observed (p = 0.87). DISCUSSION: In patients with LVO presenting within 4.5 hours of symptom onset, earlier thrombolytic administration increased successful reperfusion rates. Compared with alteplase, tenecteplase was associated with a higher probability of lytic-induced reperfusion, independent of onset-to-lytic administration times. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifiers: NCT02388061, NCT03340493. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among patients with LVO receiving a thrombolytic, reperfusion was more likely with tenecteplase than alteplase.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults.

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aß) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aß 1-42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer's Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aß or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke.

Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.

Multi-Omic Blood Biomarkers as Dynamic Risk Predictors in Late-Onset Alzheimer's Disease.

Late-onset Alzheimer's disease is the leading cause of dementia worldwide, accounting for a growing burden of morbidity and mortality. Diagnosing Alzheimer's disease before symptoms are established is clinically challenging, but would provide therapeutic windows for disease-modifying interventions. Blood biomarkers, including genetics, proteins and metabolites, are emerging as powerful predictors of Alzheimer's disease at various timepoints within the disease course, including at the preclinical stage. In this review, we discuss recent advances in such blood biomarkers for determining disease risk. We highlight how leveraging polygenic risk scores, based on genome-wide association studies, can help stratify individuals along their risk profile. We summarize studies analyzing protein biomarkers, as well as report on recent proteomic- and metabolomic-based prediction models. Finally, we discuss how a combination of multi-omic blood biomarkers can potentially be used in memory clinics for diagnosis and to assess the dynamic risk an individual has for developing Alzheimer's disease dementia.

Prevalence of cerebral microbleeds in Alzheimer's disease, dementia with Lewy bodies and Parkinson's disease dementia: A systematic review and meta-analysis.

Cerebral microbleeds (CMB) are often associated with vascular risk factors and/or cerebral amyloid angiopathy and are frequently identified in people with dementia. The present study therefore aimed to estimate the pooled prevalence and associations of CMB in Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), using meta-analytic methods. Sixty-five MRI studies were included after a systematic search on major electronic databases. We found that the prevalence of CMB was comparable across the three dementia subtypes (31-36%) and was highly influenced by the MRI techniques used. CMB in AD were associated with a history of hypertension and amyloid-ß burden. In contrast, CMB in DLB, despite being predominantly lobar, were associated with hypertension, but not amyloid-ß burden. These findings suggest that the underlying pathophysiology of CMB in DLB might differ from that of AD. There was substantially larger number of AD studies identified and more studies evaluating CMB in Lewy body dementias are warranted.

Tau in dementia with Lewy bodies.

OBJECTIVE: Neurofibrillary tangles are present in a proportion of people with dementia with Lewy bodies and may be associated with worse cognition. Recent advances in biomarkers for Alzheimer's disease include second-generation tau positron emission tomography as well as the detection of phosphorylated tau at threonine 181 (p-tau181) in plasma. This study aimed to investigate tau in people with dementia with Lewy bodies using a second-generation tau positron emission tomography tracer as well as plasma p-tau181. METHODS: Twenty-seven participants (mean age 74.7 ± 5.5) with clinically diagnosed probable dementia with Lewy bodies underwent comprehensive clinical assessment and positron emission tomography imaging (18F-MK6240 and 18F-NAV4694). Plasma p-tau181 levels were measured using Simoa technology. RESULTS: Five dementia with Lewy bodies participants (18.5%) had an abnormal tau positron emission tomography (increased tau uptake in the temporal meta-region-of-interest). Higher plasma p-tau181 concentrations correlated with higher tau deposition in the temporal region (ρ = 0.46, 95% confidence interval = [0.10, 0.72]) and classified abnormal tau positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.95 (95% confidence interval = [0.86, 0.99]). Plasma p-tau181 also correlated positively with cortical amyloid-beta binding (ρ = 0.68, 95% confidence interval = [0.40, 0.84]) and classified abnormal amyloid-beta positron emission tomography in dementia with Lewy bodies with an area under the curve of 0.91 (95% confidence interval = [0.79, 0.99]). There was no association found between tau deposition and any of the clinical variables. CONCLUSIONS: Tau is a common co-pathology in dementia with Lewy bodies. Plasma p-tau181 correlated with abnormal tau and amyloid-beta positron emission tomography and may potentially be used as a marker to identify co-morbid Alzheimer's disease-related pathology in dementia with Lewy bodies. The clinical implications of tau in dementia with Lewy bodies need to be further evaluated in larger longitudinal studies.

Exploring the Potential Association Between Self-Reported Psychological Stress and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease in Midlife: A Cross-Sectional Study.

Psychological stress is associated with dementia risk. However, the underlying mechanisms are unclear. This cross-sectional study examined the association between self-reported psychological stress and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegeneration in 73 cognitively unimpaired middle-aged adults from the Healthy Brain Project (mean age = 58±7 years). Linear regression analyses did not reveal any significant associations of psychological stress with CSF amyloid-ß42, phosphorylated tau-181, total tau, or neurofilament light chain. Cohen's f2 effect sizes were small in magnitude (f2≤0.08). Further research is needed to replicate our findings, particularly given that the sample reported on average low levels of stress.

Associations of Perceived Stress and Psychological Resilience With Cognition and a Modifiable Dementia Risk Score in Middle-Aged Adults.

OBJECTIVES: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined. METHODS: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors. RESULTS: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score. DISCUSSION: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk.

Investigation of Inflammation in Lewy Body Dementia: A Systematic Scoping Review.

Inflammatory mechanisms are increasingly recognized as important contributors to the pathogenesis of neurodegenerative diseases, including Lewy body dementia (LBD). Our objectives were to, firstly, review inflammation investigation methods in LBD (dementia with Lewy bodies and Parkinson's disease dementia) and, secondly, identify alterations in inflammatory signals in LBD compared to people without neurodegenerative disease and other neurodegenerative diseases. A systematic scoping review was performed by searching major electronic databases (MEDLINE, Embase, Web of Science, and PSYCHInfo) to identify relevant human studies. Of the 2509 results screened, 80 studies were included. Thirty-six studies analyzed postmortem brain tissue, and 44 investigated living subjects with cerebrospinal fluid, blood, and/or brain imaging assessments. Largely cross-sectional data were available, although two longitudinal clinical studies investigated prodromal Lewy body disease. Investigations were focused on inflammatory immune cell activity (microglia, astrocytes, and lymphocytes) and inflammatory molecules (cytokines, etc.). Results of the included studies identified innate and adaptive immune system contributions to inflammation associated with Lewy body pathology and clinical disease features. Different signals in early and late-stage disease, with possible late immune senescence and dystrophic glial cell populations, were identified. The strength of these associations is limited by the varying methodologies, small study sizes, and cross-sectional nature of the data. Longitudinal studies investigating associations with clinical and other biomarker outcomes are needed to improve understanding of inflammatory activity over the course of LBD. This could identify markers of disease activity and support therapeutic development.

CSF Aß42 and tau biomarkers in cognitively unimpaired Aß- middle-aged and older APOE ε4 carriers.

This study aimed to determine the relationship between the apolipoprotein E (APOE) ε4 allele and cerebrospinal fluid (CSF) and neuroimaging biomarkers of Alzheimer's disease, and cognition in cognitively unimpaired (CU) middle-aged adults (n = 82; Mage = 58.2), and in Aß- CU older adults (n = 71; Mage = 71.8). Aß- CU middle-aged ε4 carriers showed lower CSF Aß42 levels, higher levels of CSF total tau (t-tau) and neurofilament light (NfL), and poorer cognitive performance compared to noncarriers (Cohen's d: 0.30-0.56). In Aß- CU older adults, ε4 carriers also had lower CSF Aß42 levels and higher levels of CSF t-tau and p-tau181, compared to noncarriers (Cohen's d: 0.65-0.74). In both Aß- middle-aged and older adults, hippocampal and total brain volume were equivalent between ε4 carriers and noncarriers. In Aß- CU middle-aged adults, APOE ε4 is associated with decreased levels of Aß, increased tau and NfL, and poorer cognition. Similar relationships were observed in Aß- CU older adults. These results have implications for understanding clinicopathological relationships between APOE ε4 and the emergence of cognitive and biomarker abnormalities in Aß- adults.

Multidomain modifiable dementia risk factors are associated with poorer cognition in midlife.

OBJECTIVE: Studies of modifiable dementia risk factors (MDRFs) generally consider MDRFs individually, despite strong evidence that they co-occur in adult populations. In a large sample of middle-aged adults, this study aimed to determine the frequency and co-occurrence of MDRFs, spanning five domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology). The relationship between number of domains in which MDRFs were reported with cognitive performance and subjective cognitive concerns was then determined. METHOD: Middle-aged adults (n = 1,610) enrolled in the Healthy Brain Project and completed self-report surveys about their health and lifestyle. Participants also completed the Cogstate Brief Battery and the Cognitive Function Instrument, a measure of subjective ratings of cognition. Participants were classified according to number of domains (mood symptomatology, risky lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology) in which they reported at least one MDRF (0-5). Age, sex, education, and ethnicity were adjusted for in analyses. RESULTS: Most individuals (66.5%) reported MDRFs in two or more domains. Compared with individuals displaying no MDRFs, individuals with MDRFs in 3-5 domains showed worse learning/working memory performance and greater subjective cognitive concerns, with the magnitude of these differences moderate-to-large (d = 0.30-0.93). Individuals displaying MDRFs in five domains also showed worse attention/psychomotor function (d = 0.58) compared to those displaying no MDRFs. CONCLUSIONS: These findings may suggest that multidomain MDRFs are highly frequent in middle-aged adults and are related to poorer cognition. This supports that modifiable dementia risk is multidimensional and raises the possibility that multidomain behavioral intervention trials in middle-aged adults may be useful to delay or prevent cognitive impairment or decline. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Safety and Efficacy of Tenecteplase and Alteplase in Patients With Tandem Lesion Stroke: A Post Hoc Analysis of the EXTEND-IA TNK Trials.

BACKGROUND AND OBJECTIVES: The safety and efficacy of tenecteplase (TNK) in patients with tandem lesion (TL) stroke is unknown. We performed a comparative analysis of TNK and alteplase in patients with TLs. METHODS: We first compared the treatment effect of TNK and alteplase in patients with TLs using individual patient data from the EXTEND-IA TNK trials. We evaluated intracranial reperfusion at initial angiographic assessment and 90-day modified Rankin scale (mRS) with ordinal logistic and Firth regression models. Because 2 key outcomes, mortality and symptomatic intracranial hemorrhage (sICH), were few in number among those who received alteplase in the EXTEND-IA TNK trials, we generated pooled estimates for these outcomes by supplementing trial data with estimates of incidence obtained through a meta-analysis of studies identified in a systematic review. We then calculated unadjusted risk differences to compare the pooled estimates for those receiving alteplase with the incidence observed in the trial among those receiving TNK. RESULTS: Seventy-one of 483 patients (15%) in the EXTEND-IA TNK trials possessed a TL. In patients with TLs, intracranial reperfusion was observed in 11/56 (20%) of TNK-treated patients vs 1/15 (7%) alteplase-treated patients (adjusted odds ratio 2.19; 95% CI 0.28-17.29). No significant difference in 90-day mRS was observed (adjusted common odds ratio 1.48; 95% CI 0.44-5.00). A pooled study-level proportion of alteplase-associated mortality and sICH was 0.14 (95% CI 0.08-0.21) and 0.09 (95% CI 0.04-0.16), respectively. Compared with a mortality rate of 0.09 (95% CI 0.03-0.20) and an sICH rate of 0.07 (95% CI 0.02-0.17) in TNK-treated patients, no significant difference was observed. DISCUSSION: Functional outcomes, mortality, and sICH did not significantly differ between patients with TLs treated with TNK and those treated with alteplase. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that TNK is associated with similar rates of intracranial reperfusion, functional outcome, mortality, and sICH compared with alteplase in patients with acute stroke due to TLs. However, the CIs do not rule out clinically important differences. TRIAL REGISTRATION INFORMATION: clinicaltrials.gov/ct2/show/NCT02388061; clinicaltrials.gov/ct2/show/NCT03340493.

Tenecteplase Treatment and Thrombus Characteristics Associated With Early Reperfusion: An EXTEND-IA TNK Trials Analysis.

BACKGROUND: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke). METHODS: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015-2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models. RESULTS: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03-4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50-10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16-2.06]; Pinteraction=0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00-8.05] versus absent: aOR, 1.98 [95% CI, 0.65-6.03]; Pinteraction=0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25-11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01-3.83]; Pinteraction=0.16). CONCLUSIONS: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Insomnia Symptoms and Biomarkers of Alzheimer's Disease in the Community.

BACKGROUND: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer's disease remains equivocal. OBJECTIVE: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer's disease biomarkers in a cognitively unimpaired middle-aged community sample. METHODS: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia's core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aß42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOEɛ4 genotype. RESULTS: Higher ISI score was associated with greater average levels of CSF Aß42 (per point: 30.7 pg/mL, 95% CI: 4.17-57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48-223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55-192, p < 0.001). Difficulty initiating sleep was not associated with CSF Aß42, nor were insomnia features associated with p-tau181, total-tau, or NfL levels. CONCLUSION: Insomnia symptoms were associated with higher CSF Aß42 levels in this relatively young, cognitively unimpaired sample. These findings may reflect increased amyloid production due to acute sleep disruption.

Association between amyloid-beta deposition and cortical thickness in dementia with Lewy bodies.

OBJECTIVE: Amyloid-beta often co-exists in dementia with Lewy bodies, but its clinical relevance in dementia with Lewy bodies remains unclear. This study aimed to investigate the clinical and imaging correlates of amyloid-beta deposition in dementia with Lewy bodies, particularly its relationship with cortical thickness in Alzheimer's disease-prone regions and hippocampal volume. METHODS: Twenty-four participants with probable dementia with Lewy bodies underwent high-resolution magnetic resonance imaging and amyloid-beta positron emission tomography imaging using the radiotracer 18F-NAV4694. Amyloid-beta deposition was quantified and reported using the Centiloid method. RESULTS: Amyloid-beta positivity, defined as Centiloid > 50, was present in 45.8% of dementia with Lewy bodies participants. There were no statistically significant differences in clinical characteristics between Aß+ and Aß- dementia with Lewy bodies. Compared with the Aß- group, Aß+ dementia with Lewy bodies exhibited greater global cortical thinning as well as in the Alzheimer's disease-prone region of interest, adjusted for age, sex and years of education. A mean cortical thickness of 5.12 mm across a combined meta-region of interest has a sensitivity of 88.9% and specificity of 90.0% in discriminating Aß+ from Aß- dementia with Lewy bodies. Hippocampal volume was not different between groups. CONCLUSION: Early structural changes in cortical thickness, but not hippocampal volume, were observed in dementia with Lewy bodies with significant amyloid-beta burden. This may represent an early Alzheimer's disease-related neurodegenerative process.

Thrombectomy Outcomes With General vs Nongeneral Anesthesia: A Pooled Patient-Level Analysis From the EXTEND-IA Trials and SELECT Study.

BACKGROUND AND OBJECTIVES: The effect of anesthesia choice on endovascular thrombectomy (EVT) outcomes is unclear. Collateral status on perfusion imaging may help identify the optimal anesthesia choice. METHODS: In a pooled patient-level analysis of EXTEND-IA, EXTEND-IA TNK, EXTEND-IA TNK part II, and SELECT, EVT functional outcomes (modified Rankin Scale score distribution) were compared between general anesthesia (GA) vs non-GA in a propensity-matched sample. Furthermore, we evaluated the association of collateral flow on perfusion imaging, assessed by hypoperfusion intensity ratio (HIR) - Tmax > 10 seconds/Tmax > 6 seconds (good collaterals - HIR < 0.4, poor collaterals - HIR ≥ 0.4) on the association between anesthesia type and EVT outcomes. RESULTS: Of 725 treated with EVT, 299 (41%) received GA and 426 (59%) non-GA. The baseline characteristics differed in presentation National Institutes of Health Stroke Scale score (median [interquartile range] GA: 18 [13-22], non-GA: 16 [11-20], p < 0.001) and ischemic core volume (GA: 15.0 mL [3.2-38.0] vs non-GA: 9.0 mL [0.0-31.0], p < 0.001). In addition, GA was associated with longer last known well to arterial access (203 minutes [157-267] vs 186 minutes [138-252], p = 0.002), but similar procedural time (35.5 minutes [23-59] vs 34 minutes [22-54], p = 0.51). Of 182 matched pairs using propensity scores, baseline characteristics were similar. In the propensity score-matched pairs, GA was independently associated with worse functional outcomes (adjusted common odds ratio [adj. cOR]: 0.64, 95% CI: 0.44-0.93, p = 0.021) and higher neurologic worsening (GA: 14.9% vs non-GA: 8.9%, aOR: 2.10, 95% CI: 1.02-4.33, p = 0.045). Patients with poor collaterals had worse functional outcomes with GA (adj. cOR: 0.47, 95% CI: 0.29-0.76, p = 0.002), whereas no difference was observed in those with good collaterals (adj. cOR: 0.93, 95% CI: 0.50-1.74, p = 0.82), p interaction: 0.07. No difference was observed in infarct growth overall and in patients with good collaterals, whereas patients with poor collaterals demonstrated larger infarct growth with GA with a significant interaction between collaterals and anesthesia type on infarct growth rate (p interaction: 0.020). DISCUSSION: GA was associated with worse functional outcomes after EVT, particularly in patients with poor collaterals in a propensity score-matched analysis from a pooled patient-level cohort from 3 randomized trials and 1 prospective cohort study. The confounding by indication may persist despite the doubly robust nature of the analysis. These findings have implications for randomized trials of GA vs non-GA and may be of utility for clinicians when making anesthesia type choice. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that use of GA is associated with worse functional outcome in patients undergoing EVT. TRIAL REGISTRATION INFORMATION: EXTEND-IA: ClinicalTrials.gov (NCT01492725); EXTEND-IA TNK: ClinicalTrials.gov (NCT02388061); EXTEND-IA TNK part II: ClinicalTrials.gov (NCT03340493); and SELECT: ClinicalTrials.gov (NCT02446587).

Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-Level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort.

OBJECTIVE: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship. METHODS: In a pooled, patient-level analysis of the EXTEND-IA trials and SELECT study, we used a mediation analysis framework to quantify infarct growth and cerebral edema (midline shift) mediation effect on successful reperfusion (modified Treatment in Cerebral Ischemia ≥ 2b) association with functional outcome (modified Rankin Scale distribution). Furthermore, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift. RESULTS: A total 542 of 665 (81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful versus unsuccessful reperfusion. Median infarct growth was 12.3ml (interquartile range [IQR] = 1.8-48.4), and median midline shift was 0mm (IQR = 0-2.2). Of 249 (37%) demonstrating a midline shift of ≥1mm, median shift was 2.75mm (IQR = 1.89-4.21). Successful reperfusion was associated with reductions in both predefined mediators, infarct growth (ß = -1.19, 95% confidence interval [CI] = -1.51 to -0.88, p < 0.001) and midline shift (adjusted odds ratio = 0.36, 95% CI = 0.23-0.57, p < 0.001). Successful reperfusion association with improved functional outcome (adjusted common odds ratio [acOR] = 2.68, 95% CI = 1.86-3.88, p < 0.001) became insignificant (acOR = 1.39, 95% CI = 0.95-2.04, p = 0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect, respectively. Analysis considering an alternative hypothesis demonstrated consistent results. INTERPRETATION: In this mediation analysis from a pooled, patient-level cohort, a significant proportion (~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect, and identify novel therapeutic targets to further enhance reperfusion benefits. ANN NEUROL 2023;93:793-804.