Neurology最新文献

Background and objectives: The availability of disease-modifying therapies for 5q-associated spinal muscular atrophy (SMA) has heightened the need to identify suitable biomarkers. This study investigates neurofilament light chain (NfL) concentrations during long-term nusinersen treatment in adult SMA.

Methods: In a retrospective study of prospectively collected data, NfL concentrations in the CSF (cNfL) and serum (sNfL) were measured in patients with SMA from 8 German centers and in neurologic controls using a single-molecule array (Simoa) assay. NfL concentrations and clinical characteristics, including the clinical scores Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R), were analyzed for defined treatment intervals (T1-T4 [loading phase until 4 months], T5-T8 [until 23 months], T9-T12 [until 37 months], and T13-T19 [until 60 months]). Linear mixed models with a random intercept were used to assess the changes in NfL levels during treatment, considering time and covariates as fixed effects.

Results: One hundred thirteen adult patients with SMA (median age 35, 46% female), with a treatment duration of maximum 60 months, and 52 controls were included. At baseline, NfL concentrations were significantly higher in SMA {cNfL median, 585 (interquartile range [IQR] 428-787) pg/mL; sNfL, 11 (IQR 8-14) pg/mL} than in controls (cNfL, 420 [IQR 323-662] pg/mL; sNfL, 8 [IQR 6-12] pg/mL) (cNfL, p = 0.021; sNfL, p = 0.030). Median differences for all clinical scores were the highest for T5-T8 compared with the loading phase (Δ HFMSE, 0.6 [IQR 0.1-1.4], p = 0.017; Δ RULM, 0.9 [IQR 0.4-1.3], p < 0.001; Δ ALSFRS-R, 0.7 [IQR 0.4-1.0], p < 0.001), but not for subsequent intervals. Longitudinal analysis revealed a significant decrease of NfL concentrations during each treatment interval compared with the loading phase (p < 0.05, respectively) except for sNfL in T13-T19. Even among patients with no measurable clinical improvement (Δ HFMSE ≤ 0), more than 50% showed declining cNfL and sNfL levels up to T13-T19.

Discussion: NfL decreased during nusinersen treatment, suggesting its potential as a pharmacodynamic response marker in adult SMA. However, in patients without detectable clinical improvement, our study cannot determine whether they represent a more sensitive outcome measure or are not clinically meaningful.

Background and objectives: This review systematically evaluates and incorporates evidence for the use of epidural steroid injections (ESIs) in cervical and lumbar spinal stenosis and radiculopathies, assessing short-term (≤3 months) and long-term (≥6 months) improvements in pain and disability.

Methods: We searched databases for randomized controlled trials (RCTs) on the efficacy of ESIs published between January 2005 and January 2021. Data analysis was performed by American Academy of Neurology methodologists. A panel of ESI experts was engaged to interpret the evidence in a clinical context. Owing to the great variability in efficacy measures used in the articles, we report differences based on any measure of success: the success rate difference (SRD).

Results: Ninety RCTs met inclusion criteria. In cervical and lumbar radiculopathies, ESIs probably reduce short-term pain (SRD -24.0%, 95% CI -34.9 to -12.6, number needed to treat [NNT] 4) and disability (SRD -16.0%, 95% CI -26.6 to -5, NNT 6) and possibly decrease long-term disability (SRD -11.1%, 95% CI -25.3 to 3.6, NNT 9). There is insufficient evidence to determine whether ESIs reduce long-term pain in radiculopathies (SRD -10.3%, 95% CI -27.8 to 7.6). In lumbar spinal stenosis, ESIs possibly reduce short-term (SRD -26.2%, 95% CI -52.4 to 3.6, NNT 4) and long-term (SRD -11.8%, 95% CI -26.9 to 3.8, NNT 8) disability, but not short-term pain (SRD -3.5%, 95% CI -12.6 to 5.6). In lumbar stenosis, there is insufficient evidence to determine whether ESIs reduce long-term pain (SRD -6.5%, 95% CI -22.5 to 9.8). For cervical spinal stenosis, evidence is insufficient to determine the effectiveness of ESIs.

Discussion: The review affirms limited efficacy of ESIs in reducing pain and disability in cervical and lumbar radiculopathies and possibly in lumbar spinal stenosis, largely in the short term. The heterogeneity of outcome measures reported preclude presenting integrated data regarding effect size. There is controversy regarding the appropriate choice of inactive comparator treatments as a true placebo in clinical trials of ESIs. The panel recommends that future trials of ESIs use minimal meaningful clinical difference as the measure of efficacy and paraspinal muscle injection of saline as an inactive placebo.

Background and objectives: Early intensive systolic blood pressure (SBP) reduction is a promising strategy for intracerebral hemorrhage (ICH), but the optimal magnitude of reduction in the first 2 hours remains uncertain. This study aimed to determine the optimal SBP reduction magnitude to maximize benefit in patients enrolled in the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial.

Methods: We performed a post hoc analysis of the ATACH-2 trial. Participants with baseline SBP ≥180 mm Hg were randomized within 4.5 hours from onset and assigned to the intensive or standard group. The magnitude of SBP reduction was calculated as admission SBP minus minimum SBP at 2 hours. Eligible participants were divided into 5 groups by 15 mm Hg stratum: <40, 40-55, 55-70, 70-85, and ≥85 mm Hg. Poor functional outcome was defined as the modified Rankin Scale score at 3-6 and hematoma expansion (HE) as a relative increase of >33% from baseline to 24 hours. Multivariable logistic regression assessed associations between SBP reduction and outcomes.

Results: Our study included 925 patients, of whom 360 (38.9%) were female. The median age was 62 years (IQR: 53-71). The median hematoma volume was 10.2 mL (IQR: 5.1-18.4), and the median magnitude of SBP reduction was 68 mm Hg (IQR: 48-88). Of those, 209 (22.6%) experienced HE, 122 (13.2%) experienced acute kidney injury (AKI), and 516 (55.8%) had poor outcome. Hematoma expansion decreased linearly as the magnitude of blood pressure reduction increased in 5 SBP reduction groups (p < 0.001). After multivariable adjustment, patients with a greater degree of SBP reduction (≥70 mm Hg) were less likely to experience HE and a SBP reduction ≥55 mm Hg was associated with a lower risk of poor outcomes (odds ratio [OR] 0.49, 95% CI 0.28-0.85). However, a SBP reduction ≥85 mm Hg increased AKI risk compared with <40 mm Hg (OR, 2.00; 95% CI 1.01-3.94).

Discussion: Targeting a SBP reduction within the range of 55-85 mm Hg during the first 2 hours seems to be associated with optimal outcomes in patients with mild-to-moderate ICH, balancing the need to limit hematoma growth while avoiding adverse effect. Further study focusing on severe ICH is warranted.

Trial registration information: Clinical trial registration number: NCT01176565.

Classification of evidence: This post hoc analysis of the ATACH-2 trial provides Class III evidence that SBP reduction of 55-85 mm Hg during the initial 2 hours is associated with lower frequency of HE and better functional outcomes in patients with acute cerebral hemorrhage.

Background and objectives: Lifestyle behaviors, including engagement in complex mental activities, have been associated with dementia risk and neuroimaging markers of aging and Alzheimer disease. However, the life period(s) at which lifestyle factors have the greatest influence on brain health remains unclear. Our objective was to determine the relative influence of lifestyle (i.e., engagement in complex mental activities) at different life periods on older adults' brain health.

Methods: This observational study included community-dwelling cognitively unimpaired seniors (older than 65 years) from the Age-Well randomized controlled trial (Caen, France). All participants completed at baseline the Lifetime of Experiences Questionnaire, assessing engagement in complex mental activities during young adulthood (13-30 years: LEQ-young), midlife (30-65 years: LEQ-midlife), and late-life (older than 65 years: LEQ-late). LEQ scores were divided into specific and non-specific activities. Multiple regressions were conducted including LEQ scores at the 3 life periods (same model) to predict gray matter volume (GMv; structural-MRI), glucose metabolism (fluorodeoxyglucose-PET), perfusion (early-Florbetapir-PET), or amyloid burden (late-Florbetapir-PET), both in AD-signature regions and voxel-wise (significance for voxel-wise analyses: p < 0.005_uncorrected, k > 100). Correlations between LEQ and neuroimaging outcomes were then compared between (1) life periods and (2) specific and non-specific activities. Analyses were controlled for age and sex.

Results: In 135 older adults (mean age = 69.3 years; women = 61.5%), no associations were found within AD-signature regions (all p > 0.25). Voxel-wise analyses revealed no association between LEQ-young and neuroimaging. LEQ-midlife showed stronger voxel-wise associations than the other periods with GMv, notably in the anterior cingulate cortex, and with amyloid burden in the precuneus. These correlations were stronger for the LEQ-midlife specific (i.e., occupation) than the non-specific subscore (GMv: z = 3.25, p < 0.001, 95% CI [0.1292-0.5135]; amyloid: z = -1.88, p < 0.05, 95% CI [-0.3810 to -0.0113]). LEQ-late showed stronger voxel-wise associations than the other periods with perfusion and glucose metabolism in medial frontal regions. The correlation of perfusion with LEQ-late was stronger for non-specific than specific subscore (z = 2.88, p < 0.01, 95% CI [0.0894-0.4606]).

Discussion: Lifestyle at different life periods may have complementary benefits on brain health in regions related to reserve/resilience in aging. While past (midlife) engagement could promote resistance against structural/pathologic alterations, current (late-life) engagement could enhance cognitive reserve. Future larger longitudinal studies should explore mechanisms by which lifestyle promotes reserve.

Background and objectives: With upcoming clinical trials targeting preclinical stages of genetic frontotemporal dementia (FTD), early detection through cognitive screening is crucial. The Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) have potential as screening instruments for early-stage genetic FTD. However, no comparative evaluation has been performed. We aimed to compare MMSE and MoCA performance among presymptomatic, prodromal, and symptomatic pathogenic variant carriers to analyze which screening test has superior discriminative abilities.

Methods: We used cross-sectional and longitudinal data from 2 longitudinal genetic FTD cohort studies in the Netherlands and the United Kingdom, collected between 2021 and 2024. Participants were either presymptomatic, prodromal, or symptomatic pathogenic variant carriers or healthy controls (first-degree family members without pathogenic variants for FTD). Grouping was based on the global CDR-plus-NACC-FTLD score. Participants were assessed with both MoCA and MMSE. Statistical analyses compared total and subscores between groups and evaluated predictive and classification accuracy of both tests.

Results: A total of 243 participants (mean age 49.9 ± 13.1 years, mean education 14.5 ± 3.0 years, 56% female), 157 of whom were pathogenic variant carriers (MAPT, GRN, C9orf72, TARDBP, and TBK1) and 86 controls, were included. Carriers were classified as presymptomatic (n = 119), prodromal (n = 18), or symptomatic (n = 20). Both MoCA [F(3,239) = 16.565, p < 0.001] and MMSE [F(3,239) = 13.529, p < 0.001] total scores differed significantly between groups, with controls (median MoCA 28.5, 95% CI 28.0-29.0; median MMSE 30, 95% CI 30.0-30.0) outperforming prodromal (median MoCA 26, 95% CI 23.0-27.0; median MMSE 29, 95% CI 27.5-29.5) and symptomatic (median MoCA 20.5, 95% CI 17.0-24.0; median MMSE 26, 95% CI 23.5-29.0) carriers. MoCA distinguished between presymptomatic carriers and controls (median MoCA 28, 95% CI 27.0-29.0), but MMSE did not. MoCA demonstrated superior discriminative ability compared with MMSE (MoCA area under the curve [AUC] = 0.87, 95% CI 0.81-0.94; MMSE AUC = 0.80, 95% CI 0.72-0.89).

Discussion: Its higher sensitivity and better discriminative power make MoCA a more valuable tool for cognitive screening in upcoming clinical trials targeting preclinical FTD. Future studies should aim for larger sample sizes from additional study centers.

Background and objectives: Genetic testing is critical for optimal diagnosis and management of pediatric neurology patients, but access is challenging. We investigated whether social determinants of health (SDOH) were associated with genetic testing among pediatric neurology patients in a retrospective observational study.

Methods: Electronic health record data were extracted from pediatric outpatients (0-18 years) evaluated at a single tertiary care institution between July 2018 and January 2020. Genetic testing requests, insurance denials, and test completion rates were compared among non-Hispanic single-racial or multiracial Black (Black) vs non-Hispanic single-racial White (White) patients. SDOH and clinical variables including ethnoracial identity, insurance type, Area Deprivation Index, rural urban commuting area, sex, age, diagnoses, and number of neurology visits were evaluated to identify associations with chromosomal microarray (CMA), multigene panel (MGP), and exome/genome sequencing (ES/GS) test completion.

Results: Of 11,371 patients (mean age 9.25 years; 46.1% female), 554 (4.9%) completed ≥1 genetic test in the study interval, with White patients nearly twice as likely to have completed ≥1 genetic test compared with Black patients (aOR 1.88, 95% CI 1.41-2.51). Outpatient pediatric neurology was the most common specialty through which testing was completed. Neurology provider request rates for genetic testing did not differ by patient ethnoracial identity, but insurance denial rates after neurology request were lower for White vs Black patients (relative rate ratio [RR] 0.44, 95% CI 0.27-0.73), and those with public insurance were less likely to complete genetic testing after it was requested through neurology (aOR 0.59, 95% CI 0.35-0.97). However, when considering individual genetic test types completed through any specialty, insurance type was significantly associated only with MGP completion (public vs private OR 0.56, 95% CI 0.40-0.77), not CMA or ES/GS.

Discussion: Marked ethnoracial disparities in genetic testing completion were identified despite equivalent rates of genetic testing requests by neurologists. While Black patients had higher rates of insurance denials, insurance type itself accounted for the disparity in MGP but not CMA or ES/GS completion. Other unmeasured barriers stemming from systemic racism likely affected genetic testing among Black patients.