Tau as a Biomarker of Neurodegeneration Holper, Sarah; Watson, Rosie; Yassi, Nawaf
International journal of molecular sciences,
06/2022, Letnik:
23, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Less than 50 years since tau was first isolated from a porcine brain, its detection in femtolitre concentrations in biological fluids is revolutionizing the diagnosis of neurodegenerative diseases. ...This review highlights the molecular and technological advances that have catapulted tau from obscurity to the forefront of biomarker diagnostics. Comprehensive updates are provided describing the burgeoning clinical applications of tau as a biomarker of neurodegeneration. For the clinician, tau not only enhances diagnostic accuracy, but holds promise as a predictor of clinical progression, phenotype, and response to drug therapy. For patients living with neurodegenerative disorders, characterization of tau dysregulation could provide much-needed clarity to a notoriously murky diagnostic landscape.
The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may ...be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.
We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.
After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval CI, 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.
Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).
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.
•Globally, there was a significant correlation between healthy life expectancy (HALE), non-communicable disease DALYs and mortality, with COVID-19 caseload and deaths.•There was a positive ...independent association between HALE and COVID-19 cases.•The number of tourists was also associated with COVID-19 mortality.•Our integrated model of global data is valuable for health policymakers, allowing for the implementation of optimal preventative measures at national and global scales.
The interaction between coronavirus disease 2019 (COVID-19) and non-communicable diseases may increase the global burden of disease. We assessed the association of COVID-19 with ageing and non-communicable diseases.
We extracted data regarding non-communicable disease, particularly cardiovascular disease, deaths, disability-adjusted life years (DALYs), and healthy life expectancy (HALE) from the Global Burden of Disease Study (GBD) 2017. We obtained data of confirmed COVID-19 cases, deaths, and tests from the Our World in Data database as of May 28, 2020. Potential confounders of pandemic outcomes analyzed include institutional lockdown delay, hemispheric geographical location, and number of tourists. We compared all countries according to GBD classification and World Bank income level. We assessed the correlation between independent variables associated with COVID-19 caseload and mortality using Spearman's rank correlation and adjusted mixed model analysis.
High-income had the highest, and the Southeast Asia, East Asia, and Oceania region had the least cases per million population (3050.60 vs. 63.86). Sub-saharan region has reported the lowest number of COVID-19 mortality (1.9). Median delay to lockdown initiation varied from one day following the first case in Latin America and Caribbean region, to 34 days in Southeast Asia, East Asia, and Oceania. Globally, non-communicable disease DALYs were correlated with COVID-19 cases (r = 0.32, p<0.001) and deaths (r = 0.37, p<0.001). HALE correlated with COVID-19 cases (r = 0.63, p<0.001) and deaths (r = 0.61, p<0.001). HALE was independently associated with COVID-19 case rate and the number of tourists was associated with COVID-19 mortality in the adjusted model.
Preventive measures against COVID-19 should protect the public from the dual burden of communicable and non-communicable diseases, particularly in the elderly. In addition to active COVID-19 surveillance, policymakers should utilize this evidence as a guide for prevention and coordination of health services. This model is timely, as many countries have begun to reduce social isolation.
High-fidelity intracranial electrode arrays for recording and stimulating brain activity have facilitated major advances in the treatment of neurological conditions over the past decade. Traditional ...arrays require direct implantation into the brain via open craniotomy, which can lead to inflammatory tissue responses, necessitating development of minimally invasive approaches that avoid brain trauma. Here we demonstrate the feasibility of chronically recording brain activity from within a vein using a passive stent-electrode recording array (stentrode). We achieved implantation into a superficial cortical vein overlying the motor cortex via catheter angiography and demonstrate neural recordings in freely moving sheep for up to 190 d. Spectral content and bandwidth of vascular electrocorticography were comparable to those of recordings from epidural surface arrays. Venous internal lumen patency was maintained for the duration of implantation. Stentrodes may have wide ranging applications as a neural interface for treatment of a range of neurological conditions.
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.
Objective
The objective of this study was to evaluate functional and safety outcomes of endovascular thrombectomy (EVT) versus medical management (MM) in patients with M2 occlusion and examine their ...association with perfusion imaging mismatch and stroke severity.
Methods
In a pooled, patient‐level analysis of 3 randomized controlled trials (EXTEND‐IA, EXTEND‐and IA‐TNK parts 1 and 2) and 2 prospective nonrandomized studies (INSPIRE and SELECT), we evaluated EVT association with 90‐day functional independence (modified Rankin Scale mRS = 0–2) in isolated M2 occlusions as compared to medical management overall and in subgroups by mismatch profile status and stroke severity.
Results
We included 517 patients (EVT = 195 and MM = 322), baseline median (interquartile range IQR) National Institutes of Health Stroke Scale (NIHSS) was 13 (8–19) in EVT versus 10 (6–15) in MM, p < 0.001. Pretreatment ischemic core did not differ (EVT = 10 0–24 ml vs MM = 9 3–21 ml, p = 0.59). Compared to MM, EVT was more frequently associated with functional independence (68.3 vs 61.6%, adjusted odds ratio aOR = 2.42, 95% confidence interval CI = 1.25–4.67, p = 0.008, inverse probability of treatment weights IPTW‐OR = 1.75, 95% CI = 1.00–3.75, p = 0.05) with a shift toward better mRS outcomes (adjusted cOR = 2.02, 95% CI:1.23–3.29, p = 0.005), and lower mortality (5 vs 10%, aOR = 0.32, 95% CI = 0.12–0.87, p = 0.025). EVT was associated with higher functional independence in patients with a perfusion mismatch profile (EVT = 70.7% vs MM = 61.3%, aOR = 2.29, 95% CI = 1.09–4.79, p = 0.029, IPTW‐OR = 2.02, 1.08–3.78, p = 0.029), whereas no difference was found in those without mismatch (EVT = 43.8% vs MM = 62.7%, p = 0.17, IPTW‐OR: 0.71, 95% CI = 0.18–2.78, p = 0.62). Functional independence was more frequent with EVT in patients with moderate or severe strokes, as defined by baseline NIHSS above any thresholds from 6 to 10, whereas there was no difference between groups with milder strokes below these thresholds.
Interpretation
In patients with M2 occlusion, EVT was associated with improved clinical outcomes when compared to MM. This association was primarily observed in patients with a mismatch profile and those with higher stroke severity. ANN NEUROL 2022;91:629–639
Intracerebral hemorrhage is a serious potential complication of stroke thrombolysis. We investigated the optimal computed tomography perfusion (CTP) parameter to predict cerebral parenchymal hematoma ...(PH) in acute ischemic stroke.
Patients with hyperacute ischemic stroke had whole-brain CTP and follow-up computed tomography/MRI to identify hemorrhagic transformation. The association of the 3 parameters relative cerebral blood flow, relative cerebral blood volume, and time to maximum (Tmax) with PH was examined using receiver operating characteristic analysis and multivariate logistic regression.
Of 132 patients, 70 were treated with thrombolysis, and 14 (10.6%) developed PH on follow-up imaging. Baseline National Institutes of Health Stroke Scale score (P=0.033) and thrombolysis (P=0.003) were both predictive of PH. Receiver operating characteristic analysis revealed that Tmax>14 s (area under the curve=0.748; P=0.002) and relative cerebral blood flow <30% of contralateral mean (area under the curve=0.689, P=0.021) were the optimal thresholds, and the Bayesian information criterion (+2.6) indicated that Tmax was more strongly associated with PH than relative cerebral blood flow. Tmax >14 s volumes of >5 mL allowed prediction of PH with sensitivity of 79%, specificity of 68%, and negative likelihood ratio of 3.16. Tmax>14 s volume and thrombolysis were both independently predictive of PH in a multivariate logistic regression model (P<0.05).
Tmax >14 s was the CTP parameter most strongly associated with PH. This outperformed relative cerebral blood flow <30%, which closely equates to CTP estimates of ischemic core volume. Although ischemic core volume on CTP is useful in the pretreatment prediction of PH, severe hypoperfusion on Tmax is more strongly associated and may allow better prediction of the likely anatomic location of hemorrhage.
Degeneration of gray matter and subcortical structures after ischemic stroke has been well described. However, little is known about white matter degeneration after stroke. It is unclear whether ...white matter degeneration occurs throughout the whole brain, or whether patterns of degeneration occur more in specific brain areas.
We prospectively collected National Institutes of Health Stroke Scale (NIHSS) scores and diffusion tensor imaging (DTI) in patients with acute ischemic stroke within the first week after onset (baseline), and at 1 and 3 months. DTI was processed to produce maps of fractional anisotropy, apparent diffusion coefficients, and axial and radial diffusivity. DTI parameters in specified regions-of-interest corresponding to items on the NIHSS were calculated and changes over time were assessed using linear mixed-effect modeling.
Seventeen patients were included in the study. Mean age (SD) was 71 (11.7) years, and median (IQR) baseline NIHSS 9 (5-13.3). Changes over time were observed in both visual cortices, contralesional primary motor cortex, premotor cortex, and superior temporal gyrus (P < .05). Changes in the ipsilesional motor cortex and inferior parietal lobule were only seen in patients with scores on the respective NIHSS-items (P < .05). No significant changes in global white matter diffusivity parameters were identified (P > .05).
White matter changes after stroke may be localized rather than a global phenomenon.
Simultaneous multiple intracerebral hemorrhages (SMICHs) are uncommon. Few single-center studies have analyzed characteristics and outcome of SMICH. We analyzed clinical characteristics and outcome ...of SMICH patients from 2 comprehensive stroke centers.
Baseline imaging from consecutive intracerebral hemorrhage (ICH) patients (n=1552) from Helsinki ICH study and Royal Melbourne Hospital ICH study was screened for SMICH. ICH pathogenesis was classified according to the structural lesion, medication, amyloid angiopathy, systemic/other disease, hypertension, undetermined classification system (SMASH-U). ICH caused by trauma, tumor, and aneurysmal rupture was excluded. Baseline clinical and radiological characteristics and 90-day mortality were compared between SMICH and single ICH patients. Association of SMICH with 90-day mortality was assessed in multivariable logistic regression models adjusted for predictors of ICH outcome.
Of 1452 patients, 85 (5.9%) were classified as SMICH. SMICH were more often female (58% versus 42%;
=0.004), had lower baseline Glasgow Coma Scale (12 versus 14;
=0.008), and more frequent lobar location (59% versus 34%;
<0.001) compared with single ICH. The SMASH-U pathogenesis of SMICH patients was less often hypertensive (20% versus 37%;
=0.001), more often systemic coagulopathy (12% versus 3%;
<0.001), and trended toward more cerebral amyloid angiopathy (32% versus 23%;
=0.071). SMICH was not associated with 90-day mortality on univariate (37% versus 35%;
=0.610), multivariable (odds ratio, 0.783; 95% confidence interval, 0.401-1.529;
=0.473), or propensity score-matched analyses (odds ratio, 0.760; 95% confidence interval, 0.352-1.638;
=0.484).
SMICH occurs in ≈1 in 20 ICH, more commonly with lobar located hematomas and systemic coagulopathy with less hypertensive angiopathy. The associated mortality is similar to single ICH. Given varied etiologies, SMICH management should target the underlying pathology.
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