Safety and efficacy of intravenous thrombolytic therapy in the extended window up to 24 hours: A systematic review and meta-analysis.

OBJECTIVE: About 25% of patients with acute ischemic stroke (AIS) present within the intravenous thrombolytic (IVT) therapeutic window of <4.5 h. This study is to elucidate the safety and efficacy of IVT in the extended therapeutic window (ETW) in patients with AIS. METHODS: Using PRISMA guidelines, a systematic review was conducted using PubMed, Embase, and Scopus. A rigorous risk of bias assessment was conducted using the RoB2 tool. Rates of excellent and good functional outcome (mRS 0-1 and mRS 0-2) at 90 days, symptomatic intracranial hemorrhage (sICH), and mortality at 90 days were pooled using generalized linear mixed model and compared with controls. Meta-analyses were conducted employing random-effect models with risk ratio (RR) and 95% confidence intervals (CIs). Subgroup analysis was performed to assess the effect of imaging modalities used for patient selection. RESULTS: Eight randomized controlled trials (n = 2221, 59% male) were included. At 90 days IVT showed higher rates of functional recovery: mRS 0-1: RR 1.21 95% CI 1.1-1.34, p < 0.001, and mRS 0-2: RR 1.11 95% CI 1.03-1.18, p = 0.004. Rate of mortality at 90 day was not different between groups: RR 1.17 95% CI 0.93-1.48, p = 0.17. However, the rate of sICH was higher among IVT group: RR 2.93 95% CI 1.53-5.6, p = 0.001. Subgroup analysis showed higher mRS 0-1 among patients who were selected based on perfusion imaging (p < 0.05). INTERPRETATION: The use of IVT in AIS in ETW is beneficial especially with the use of perfusion imaging for patients' selection.

Outcomes of mechanical thrombectomy in patients with acute ischemic stroke and thrombocytopenia: systematic review and meta-analysis.

BACKGROUND: Mechanical Thrombectomy (MT) has improved outcomes in acute ischemic stroke (AIS) due to Large Vessel Obstruction (LVO). However, there is limited data on the safety and outcomes of MT in AIS patients with thrombocytopenia. This study aims to assess the efficacy and safety of MT in this population. METHODS: Following the PRISMA guidelines, a comprehensive systematic review was conducted using PubMed, Embase, Web of Science, and Scopus. Studies meeting inclusion criteria underwent rigorous risk of bias assessment using the ROBINS-I tool. We compared outcomes between patients with and without thrombocytopenia undergoing MT. Using the R software version 4.3.1, meta-analyses were conducted employing random-effect models. RESULTS: This meta-analysis encompassed data from 5 studies. Thrombocytopenic AIS patients who underwent MT (n = 974) exhibited lower rates of functional independence (OR 0.83, 95% CI 0.71-0.98; p = 0.030) compared to patients with normal platelet counts (n = 2036). In addition, the thrombocytopenic group experienced higher mortality as compared to the group with normal platelet counts (OR 1.76, 95% CI 1.26-2.45; p < 0.001). Rates of sICH were found to be similar between groups (OR 1.20, 95% CI 0.74-1.93; p = 0.456), as were rates of successful recanalization (OR 0.94, 95% CI 0.47-1.87; p = 0.863). Lastly, no significant differences were observed in procedure times between thrombocytopenic and non-thrombocytopenic groups. CONCLUSION: As compared to patients without thrombocytopenia, thrombocytopenic AIS patients undergoing MT displayed lower functional independence and higher mortality rates, with no significant differences in sICH or successful recanalization.

Development of a protocol to assess within-subject, regional white matter hyperintensity changes in aging and dementia.

BACKGROUND: White matter hyperintensities (WMH), associated with both dementia risk and progression, can individually progress, remain stable, or even regress influencing cognitive decline related to specific cerebrovascular-risks. This study details the development and validation of a registration protocol to assess regional, within-subject, longitudinal WMH changes (ΔWMH) that is currently lacking in the field. NEW METHOD: 3D-FLAIR images (baseline and one-year-visit) were used for protocol development and validation. The method was validated by assessing the correlation between forward and reverse longitudinal registration, and between summated regional progression-regression volumes and Global ΔWMH. The clinical relevance of growth-regression ΔWMH were explored in relation to an executive function test. RESULTS: MRI scans for 79 participants (73.5 ± 8.8 years) were used in this study. Global ΔWMH vs. summated regional progression-regression volumes were highly associated (r2 = 0.90; p-value < 0.001). Bi-directional registration validated the registration method (r2 = 0.999; p-value < 0.001). Growth and regression, but not overall ΔWMH, were associated with one-year declines in performance on Trial-Making-Test-B. COMPARISON WITH EXISTING METHOD(S): This method presents a unique registration protocol for maximum tissue alignment, demonstrating three distinct patterns of longitudinal within-subject ΔWMH (stable, growth and regression). CONCLUSIONS: These data detail the development and validation of a registration protocol for use in assessing within-subject, voxel-level alterations in WMH volume. The methods developed for registration and intensity correction of longitudinal within-subject FLAIR images allow regional and within-lesion characterization of longitudinal ΔWMH. Assessing the impact of associated cerebrovascular-risks and longitudinal clinical changes in relation to dynamic regional ΔWMH is needed in future studies.

White Matter Hyperintensity Regression: Comparison of Brain Atrophy and Cognitive Profiles with Progression and Stable Groups.

Subcortical white matter hyperintensities (WMHs) in the aging population frequently represent vascular injury that may lead to cognitive impairment. WMH progression is well described, but the factors underlying WMH regression remain poorly understood. A sample of 351 participants from the Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) was explored who had WMH volumetric quantification, structural brain measures, and cognitive measures (memory and executive function) at baseline and after approximately 2 years. Selected participants were categorized into three groups based on WMH change over time, including those that demonstrated regression (n = 96; 25.5%), stability (n = 72; 19.1%), and progression (n = 209; 55.4%). There were no significant differences in age, education, sex, or cognitive status between groups. Analysis of variance demonstrated significant differences in atrophy between the progression and both regression (p = 0.004) and stable groups (p = 0.012). Memory assessments improved over time in the regression and stable groups but declined in the progression group (p = 0.003; p = 0.018). WMH regression is associated with decreased brain atrophy and improvement in memory performance over two years compared to those with WMH progression, in whom memory and brain atrophy worsened. These data suggest that WMHs are dynamic and associated with changes in atrophy and cognition.

Post-acquisition processing confounds in brain volumetric quantification of white matter hyperintensities.

BACKGROUND: Disparate research sites using identical or near-identical magnetic resonance imaging (MRI) acquisition techniques often produce results that demonstrate significant variability regarding volumetric quantification of white matter hyperintensities (WMH) in the aging population. The sources of such variability have not previously been fully explored. NEW METHOD: 3D FLAIR sequences from a group of randomly selected aged subjects were analyzed to identify sources-of-variability in post-acquisition processing that can be problematic when comparing WMH volumetric data across disparate sites. The methods developed focused on standardizing post-acquisition protocol processing methods to develop a protocol with less than 0.5% inter-rater variance. RESULTS: A series of experiments using standard MRI acquisition sequences explored post-acquisition sources-of-variability in the quantification of WMH volumetric data. Sources-of-variability included: the choice of image center, software suite and version, thresholding selection, and manual editing procedures (when used). Controlling for the identified sources-of-variability led to a protocol with less than 0.5% variability between independent raters in post-acquisition WMH volumetric quantification. COMPARISON WITH EXISTING METHOD(S): Post-acquisition processing techniques can introduce an average variance approaching 15% in WMH volume quantification despite identical scan acquisitions. Understanding and controlling for such sources-of-variability can reduce post-acquisition quantitative image processing variance to less than 0.5%. DISCUSSION: Considerations of potential sources-of-variability in MRI volume quantification techniques and reduction in such variability is imperative to allow for reliable cross-site and cross-study comparisons.

Global Cerebral Atrophy Detected by Routine Imaging: Relationship with Age, Hippocampal Atrophy, and White Matter Hyperintensities.

BACKGROUND AND PURPOSE: Interpreting the clinical significance of moderate-to-severe global cerebral atrophy (GCA) is a conundrum for many clinicians, who visually interpret brain imaging studies in routine clinical practice. GCA may be attributed to normal aging, Alzheimer's disease (AD), or cerebrovascular disease (CVD). Understanding the relationships of GCA with aging, AD, and CVD is important for accurate diagnosis and treatment decisions for cognitive complaints. METHODS: To elucidate the relative associations of age, moderate-to-severe white matter hyperintensities (WMHs), and moderate-to-severe medial temporal lobe atrophy (MTA), with moderate-to-severe GCA, we visually rated clinical brain imaging studies of 325 participants from a community based sample. Logistic regression analysis was conducted to assess the relations of GCA with age, WMH, and MTA. RESULTS: The mean age was 76.2 (±9.6) years, 40.6% were male, and the mean educational attainment was 15.1 (±3.7) years. Logistic regression results demonstrated that while a 1-year increase in age was associated with GCA (OR = 1.04; P = .04), MTA (OR = 3.7; P < .001), and WMH (OR = 8.80; P < .001) were strongly associated with GCA in our study population. Partial correlation analysis showed that the variance of GCA explained by age is less than the variance attributed to MTA and WMH (r = .13, .21, and .43, respectively). CONCLUSIONS: Moderate-to-severe GCA is most likely to occur in the presence of AD or CVD and should not be solely attributed to age when evaluating clinical imaging findings in the workup of cognitive complaints. Developing optimal diagnostic and treatment strategies for cognitive decline in the setting of GCA requires an understanding of its risk factors in the aging population.

Distinct White Matter Changes Associated with Cerebrospinal Fluid Amyloid-ß1-42 and Hypertension.

BACKGROUND: Alzheimer's disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. OBJECTIVE: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. METHODS: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer's Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aß1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. RESULTS: HTN and CSF Aß1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aß1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aß1-42 on WMH volume, but no significant HTN×CSF Aß1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aß1-42. CONCLUSION: Associations of HTN and lower CSF Aß1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology.

"New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS).

The pathology-based classification of Alzheimer's disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD "mimic," which has been termed "hippocampal sclerosis of aging" or "hippocampal sclerosis dementia." This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors (GRN, TMEM106B, ABCC9, and KCNMB2), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the "oldest-old" with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend "cerebral age-related TDP-43 and sclerosis" (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.