Evaluation of intensive versus standard blood pressure reduction and association with cognitive decline and dementia : a systematic review and metaAnalysis

Importance: Optimal blood pressure (BP) targets for the prevention of cognitive impairment remain uncertain. Objective: To explore the association of intensive (i.e. lower than usual) BP reduction compared to guidelines on the incidence of cognitive decline and dementia in adults with hypertension. Data Sources and Study Selection: We conducted a systematic review and meta-analysis of randomized controlled trials that evaluated the association of intensive systolic BP lowering on cognitive outcomes by searching MEDLINE, Embase, CENTRAL, Web of Science, CINAHL, PsycINFO, ICTRP and ClinicalTrials.gov for data up to October 27, 2020. Data Extraction and Synthesis: Data screening and extraction were performed independently by two reviewers based on PRISMA guidelines. The risk of bias was assessed using the Cochrane risk-of-bias 2 tool. We used random-effects models using the inverse variance method for our pooled analyses. We evaluated the presence of potential heterogeneity with the I2 index. Main Outcomes and Measures: Our primary outcome was cognitive decline. Secondary outcomes included the incidence of dementia, mild cognitive impairment (MCI), cerebrovascular events, serious adverse events, and all-cause mortality. Results: From 7,755 citations, we identified sixteen publications from five trials (17,396 participants, mean age 65.7 years, 60.5% males) and two additional ongoing trials. All five trials included in quantitative analyses were considered at unclear to high risk of bias. The mean followup duration was 3.3 years (range 2.0 to 4.7 years). Intensive BP reduction was not significantly associated with global cognitive performance (SMD 0.01, 95% CI -0.04 to 0.06, I2 = 0%, four trials, 5,246 patients), incidence of dementia (RR 1.09, 95% CI 0.32 to 3.67, I2 = 27%, two trials, 9,444 patients) or incidence of MCI (RR 0.91, 95% CI 0.73 to 1.14, I2 = 74%, two trials, 10,774 patients) when compared to standard treatment. However, we found a reduction of cerebrovascular events in the intensive arm (RR 0.79, 95% CI 0.67-0.93, I2 = 0%, five trials, 17,396 patients) without an increased risk of serious adverse events or mortality. Conclusions and Relevance: We did not detect a significant association between BP reduction and lower risk of cognitive decline, dementia or MCI. The certainty of this evidence is low due to the limited sample size, the risk of bias of included trials and the observed statistical heterogeneity. Hence, current available evidence does not justify the use of lower BP targets for the prevention of cognitive decline and dementi

Ex vivo drug sensitivity screening predicts response to temozolomide in glioblastoma patients and identifies candidate biomarkers

Background: Patient-derived glioma stem-like cells (GSCs) have become the gold-standard in neuro-oncological research; however, it remains to be established whether loss of in situ microenvironment affects the clinically-predictive value of this model. We implemented a GSC monolayer system to investigate in situ-in vitro molecular correspondence and the relationship between in vitro and patient response to temozolomide (TMZ). Methods: DNA/RNA-sequencing was performed on 56 glioblastoma tissues and 19 derived GSC cultures. Sensitivity to TMZ was screened across 66 GSC cultures. Viability readouts were related to clinical parameters of corresponding patients and whole-transcriptome data. Results: Tumour DNA and RNA sequences revealed strong similarity to corresponding GSCs despite loss of neuronal and immune interactions. In vitro TMZ screening yielded three response categories which significantly correlated with patient survival, therewith providing more specific prediction than the binary MGMT marker. Transcriptome analysis identified 121 genes related to TMZ sensitivity of which 21were validated in external datasets. Conclusion:GSCs retain patient-unique hallmark gene expressions despite loss of their natural environment. Drug screening using GSCs predicted patient response to TMZ more specifically than MGMT status, while transcriptome analysis identified potential biomarkers for this response. GSC drug screening therefore provides a tool to improve drug development and precision medicine for glioblastoma.</p

Severe cerebellar hemorrhage following transverse sinus stenting for idiopathic intracranial hypertension.

We report a severe adverse event occurring in the course of a cohort study (ISRCTN13784335) aimed at measuring the efficacy and safety of venous stenting in the treatment of patients with medically refractory idiopathic intracranial hypertension (IIH). The patient was a 41-year-old woman who was not overweight, who presented with severe headache, grade 1 bilateral papilledema and transient tinnitus, refractory to medical treatment. Right transverse sinus stenting was successfully performed. Following surgery, the patient’s state of consciousness decreased acutely with rapid and progressive loss of brainstem reflex. CT scan revealed acute cerebellar and intraventricular hemorrhage with obstructive hydrocephalus. Angioscan revealed normal venous sinus patency and cerebral MRI showed acute mesencephalic ischemia. Mechanical impairment of cerebellar venous drainage by the stent or venous perforation with the large guidewire used in this technique are two logical ways to explain the cerebellar hemorrhage seen in our patient. The risk of such a complication could probably be reduced using alternative tools and technique. However, given the low level of evidence around the safety of transverse sinus stenting in IIH, its formal assessment in clinical trials is required

Atherosclerotic burden findings in young cryptogenic stroke patients with and without a patent foramen ovale

BACKGROUND AND PURPOSE: To further determine the mechanisms of cryptogenic stroke or transient ischemic attack in young patients, we evaluated indices of atherosclerosis in patients <or=55 years old diagnosed with cryptogenic cerebrovascular event comparing those with patent foramen ovale (PFO) with those without PFO. METHODS: This was a prospective study including 100 consecutive patients <or=55 years old (mean age, 45+/-8 years; 56 males) diagnosed with cryptogenic stroke/transient ischemic attack. PFO was identified in 59 of these patients with the use of transesophageal echocardiography with contrast study. The following surrogate markers of atherosclerosis were evaluated in all patients: carotid intima media thickness as measured by carotid ultrasonography and endothelial function as determined by brachial flow-mediated vasodilation. The same measurements were obtained in a control group of 50 age- and sex-matched control subjects. RESULTS: Patients without PFO were more likely to be current smokers and obese and more frequently had a history of hypertension and dyslipidemia. Carotid intima media thickness measurements were higher (P<0.0001) in patients without PFO (1.03+/-0.31 mm) compared with those with PFO (0.75+/-0.20 mm) and control subjects (0.79+/-0.17 mm). The absence of PFO was also associated with lower brachial flow-mediated vasodilation (without PFO: 5.04+/-3.39%; with PFO: 7.16+/-4.09%; control subjects: 7.33+/-4.07%; P=0.02). There were no differences in carotid intima media thickness and flow-mediated vasodilation between patients with stroke/transient ischemic attack with PFO and control subjects. The presence of PFO was independently associated with reduced carotid intima media thickness (P<0.0001) and increased flow-mediated vasodilation (P=0.019). CONCLUSIONS: In patients <or=55 years old diagnosed with cryptogenic stroke/transient ischemic attack, the presence of PFO was associated with a lower atherosclerotic burden as measured by carotid intima media thickness and endothelial function with no differences compared with a control group without cerebrovascular event. These results suggest that an atherosclerotic-mediated mechanism may be involved in cryptogenic stroke/transient ischemic attack in patients without PFO, whereas a nonatherosclerotic mechanism may mediate the cerebrovascular event in the presence of PFO

Acute Isolated Dysarthria Is Associated with a High Risk of Stroke

Background: Isolated dysarthria is an uncommon presentation of transient ischemic attack (TIA)/minor stroke and has a broad differential diagnosis. There is little information in the literature about how often this presentation is confirmed to be a TIA/stroke, and therefore there is debate about the risk of subsequent vascular events. Given the uncertain prognosis, it is unclear how to best manage patients presenting to the emergency department (ED) with isolated dysarthria. The objective of this study was to prospectively identify and follow a cohort of patients presenting to EDs with isolated dysarthria in order to explore their natural history and risk of recurrent cerebrovascular events. Specifically, we sought to determine early outcomes of individuals with this nonspecific and atypical presentation in order to appropriately expedite their management. Methods: Patients with isolated dysarthria having presented to 8 Canadian EDs between October 2006 and April 2009 were analyzed as part of a prospective multicenter cohort study of patients with acute neurological symptoms as assessed by emergency physicians. The study inclusion criteria were age ≥18 years, a normal level of consciousness, and a symptom onset Results: Between 2006 and 2009, 1,528 patients were enrolled and had a 90-day follow-up. Of these, 43 patients presented with isolated acute-onset dysarthria (2.8%). Recurrent stroke occurred in 6/43 (14.0%) within 90 days of enrollment. The predicted maximal 90-day stroke rate was 9.8% (based on a median ABCD2 score of 5 for the isolated dysarthria cohort). After adjusting for covariates, isolated dysarthria independently predicted stroke within 90 days (aOR: 3.96; 95% CI: 1.3-11.9; p = 0.014). Conclusions: The isolated dysarthria cohort carried a recurrent stroke risk comparable to that predicted by the median ABCD2 scores. Although isolated dysarthria is a nonspecific and uncommon clinical presentation of TIA, these findings support the need to view it first and foremost as a vascular presentation until proven otherwise and to manage such patients as if they were at high risk of stroke in accordance with established high-risk TIA guidelines

Ninety‐Day Stroke or Transient Ischemic Attack Recurrence in Patients Prescribed Anticoagulation in the Emergency Department With Atrial Fibrillation and a New Transient Ischemic Attack or Minor Stroke

Background For patients with atrial fibrillation seen in the emergency department (ED) following a transient ischemic attack (TIA) or minor stroke, the impact of initiating oral anticoagulation immediately rather than deferring the decision to outpatient follow‐up is unknown. Methods and Results We conducted a planned secondary data analysis of a prospective cohort of 11 507 adults in 13 Canadian EDs between 2006 and 2018. Patients were eligible if they were aged 18 years or older, with a final diagnosis of TIA or minor stroke with previously documented or newly diagnosed atrial fibrillation. The primary outcome was subsequent stroke, recurrent TIA, or all‐cause mortality within 90 days of the index TIA diagnosis. Secondary outcomes included stroke, recurrent TIA, or death and rates of major bleeding. Of 11 507 subjects with TIA/minor stroke, atrial fibrillation was identified in 11.2% (1286, mean age, 77.3 [SD 11.1] years, 52.4% male). Over half (699; 54.4%) were already taking anticoagulation, 89 (6.9%) were newly prescribed anticoagulation in the ED. By 90 days, 4.0% of the atrial fibrillation cohort had experienced a subsequent stroke, 6.5% subsequent TIA, and 2.6% died. Results of a multivariable logistic regression indicate no association between prescribed anticoagulation in the ED and these 90‐day outcomes (composite odds ratio, 1.37 [95% CI, 0.74–2.52]). Major bleeding was found in 5 patients, none of whom were in the ED‐initiated anticoagulation group. Conclusions Initiating oral anticoagulation in the ED following new TIA was not associated with lower recurrence rates of neurovascular events or all‐cause mortality in patients with atrial fibrillation

Comparative analysis of deeply phenotyped GBM cohorts of 'short-term' and 'long-term' survivors.

peer reviewedBACKGROUND: Glioblastoma (GBM) is an aggressive brain cancer that typically results in death in the first 15 months after diagnosis. There have been limited advances in finding new treatments for GBM. In this study, we investigated molecular differences between patients with extremely short (≤ 9 months, Short term survivors, STS) and long survival (≥ 36 months, Long term survivors, LTS). METHODS: Patients were selected from an in-house cohort (GLIOTRAIN-cohort), using defined inclusion criteria (Karnofsky score > 70; age < 70 years old; Stupp protocol as first line treatment, IDH wild type), and a multi-omic analysis of LTS and STS GBM samples was performed. RESULTS: Transcriptomic analysis of tumour samples identified cilium gene signatures as enriched in LTS. Moreover, Immunohistochemical analysis confirmed the presence of cilia in the tumours of LTS. Notably, reverse phase protein array analysis (RPPA) demonstrated increased phosphorylated GAB1 (Y627), SRC (Y527), BCL2 (S70) and RAF (S338) protein expression in STS compared to LTS. Next, we identified 25 unique master regulators (MR) and 13 transcription factors (TFs) belonging to ontologies of integrin signalling and cell cycle to be upregulated in STS. CONCLUSION: Overall, comparison of STS and LTS GBM patients, identifies novel biomarkers and potential actionable therapeutic targets for the management of GBM