White matter hyperintensity patterns: associations with comorbidities, amyloid, and cognition.

BACKGROUND: White matter hyperintensities (WMHs) are often measured globally, but spatial patterns of WMHs could underlie different risk factors and neuropathological and clinical correlates. We investigated the spatial heterogeneity of WMHs and their association with comorbidities, Alzheimer's disease (AD) risk factors, and cognition. METHODS: In this cross-sectional study, we studied 171 cognitively unimpaired (CU; median age: 65 years, range: 50 to 89) and 51 mildly cognitively impaired (MCI; median age: 72, range: 53 to 89) individuals with available amyloid (18F-flutementamol) PET and FLAIR-weighted images. Comorbidities were assessed using the Cumulative Illness Rating Scale (CIRS). Each participant's white matter was segmented into 38 parcels, and WMH volume was calculated in each parcel. Correlated principal component analysis was applied to the parceled WMH data to determine patterns of WMH covariation. Adjusted and unadjusted linear regression models were used to investigate associations of component scores with comorbidities and AD-related factors. Using multiple linear regression, we tested whether WMH component scores predicted cognitive performance. RESULTS: Principal component analysis identified four WMH components that broadly describe FLAIR signal hyperintensities in posterior, periventricular, and deep white matter regions, as well as basal ganglia and thalamic structures. In CU individuals, hypertension was associated with all patterns except the periventricular component. MCI individuals showed more diverse associations. The posterior and deep components were associated with renal disorders, the periventricular component was associated with increased amyloid, and the subcortical gray matter structures was associated with sleep disorders, endocrine/metabolic disorders, and increased amyloid. In the combined sample (CU + MCI), the main effects of WMH components were not associated with cognition but predicted poorer episodic memory performance in the presence of increased amyloid. No interaction between hypertension and the number of comorbidities on component scores was observed. CONCLUSION: Our study underscores the significance of understanding the regional distribution patterns of WMHs and the valuable insights that risk factors can offer regarding their underlying causes. Moreover, patterns of hyperintensities in periventricular regions and deep gray matter structures may have more pronounced cognitive implications, especially when amyloid pathology is also present.

Validation of the ICEBERG emergency room screening tool for early identification of older patients with geriatric consultation needs.

Background: The growing number of older and oldest-old patients often present in the emergency room (ER) with undiagnosed geriatric syndromes posing them at high risk for complications in acute care. Objective: To develop and validate an ER screening tool (ICEBERG) to capture 9 geriatric domains of risk in older patients. Design setting and participants: For construct validity we performed a chart-based study in 129 ER patients age 70 years and older admitted to acute geriatric care (pilot 1). For criterion validity we performed a prospective study in 288 ER patients age 70 years and older admitted to acute care (pilot 2). Exposure: In both validation steps, the exposure was ICEBERG test performance below and above the median score (10, range 0-30). Outcome measures and analysis: In pilot 1, we compared the exposure with results of nine tests of the Comprehensive Geriatric Assessment (CGA). In pilot 2, we compared the exposure assessed in the ER to following length of hospital stay (LOS), one-on-one nursing care needs, in-hospital mortality, 30-day re-admission rate, and discharge to a nursing home. Main results: Mean age was 82.9 years (SD 6.7; n = 129) in pilot 1, and 81.5 years (SD 7.0; n = 288) in pilot 2. In pilot 1, scoring ≥10 was associated with significantly worse performance in 8 of 9 of the individual CGA tests. In pilot 2, scoring ≥10 resulted in longer average LOS (median 7 days, IQR 4, 11 vs. 6 days, IQR 3, 8) and higher nursing care needs (median 1,838 min, IQR 901, 4,267 vs. median 1,393 min, IQR 743, 2,390). Scoring ≥10 also increased the odds of one-on-one nursing care 2.9-fold (OR 2.86, 95%CI 1.17-6.98), and the odds of discharge to a nursing home 3.7-fold (OR 3.70, 95%CI 1.74-7.85). Further, scoring ≥10 was associated with higher in-hospital mortality and re-hospitalization rates, however not reaching statistical significance. Average time to complete the ICEBERG tool was 4.3 min (SD 1.3). Conclusion: Our validation studies support construct validity of the ICEBERG tool with the CGA, and criterion validity with several clinical indicators in acute care.

Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition.

Tissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.

Association between two distinct executive tasks in schizophrenia: a functional transcranial Doppler sonography study.

BACKGROUND: Schizophrenia is a severe mental disorder involving impairments in executive functioning, which are important cognitive processes that can be assessed by planning tasks such as the Stockings of Cambridge (SOC), and tasks of rule learning/abstraction such as the Wisconsin Card Sorting Test (WCST). We undertook this study to investigate the association between performance during separate phases of SOC and WCST, including mean cerebral blood flow velocity (MFV) measurements in chronic schizophrenia. METHODS: Functional transcranial Doppler sonography (fTCD) was used to assess bilateral MFV changes in the middle (MCA) and anterior (ACA) cerebral arteries. Twenty-two patients with chronic schizophrenia and 20 healthy subjects with similar sociodemographic characteristics performed SOC and WCST during fTCD measurements of the MCA and the ACA. The SOC was varied in terms of easy and difficult problems, and also in terms of separate phases, namely mental planning and movement execution. The WCST performance was assessed separately for maintaining set and set shifting. This allowed us to examine the impact of problem difficulty and the impact of separate phases of a planning task on distinct intervals of WCST. Simultaneous registration of MFV was carried out to investigate the linkage of brain perfusion during the tasks. RESULTS: In patients, slowing of movement execution during easy problems (SOC) was associated with slowing during maintaining set (WCST) (P < 0.01). In healthy subjects, faster planning and movement execution during predominantly difficult problems were associated with increased performance of WCST during set shifting (P < 0.01). In the MCA, patients showed a significant and positive correlation of MFV between movement execution and WCST (P < 0.01). CONCLUSION: The results of this study demonstrate performance and brain perfusion abnormalities in the association pattern of two different tasks of executive functioning in schizophrenia, and they support the notion that executive functions have a pathological functional correlate predominantly in the lateral hemispheres of the brain. This study also underpins the scientific potential of fTCD in assessing brain perfusion in patients with schizophrenia.