Different Relationship Between Systolic Blood Pressure and Cerebral Perfusion in Subjects With and Without Hypertension.

Although there is an increasing agreement that hypertension is associated with cerebrovascular compromise, relationships between blood pressure (BP) and cerebral blood flow are not fully understood. It is not known what BP level, and consequently what therapeutic goal, is optimal for brain perfusion. Moreover, there is limited data on how BP affects hippocampal perfusion, a structure critically involved in memory. We conducted a cross-sectional (n=445) and longitudinal (n=185) study of adults and elderly without dementia or clinically apparent stroke, who underwent clinical examination and brain perfusion assessment (age 69.2±7.5 years, 62% women, 45% hypertensive). Linear models were used to test baseline BP-blood flow relationship and to examine how changes in BP influence changes in perfusion. In the entire group, systolic BP (SBP) was negatively related to cortical (ß=-0.13, P=0.005) and hippocampal blood flow (ß=-0.12, P=0.01). Notably, this negative relationship was apparent already in subjects without hypertension. Hypertensive subjects showed a quadratic relationship between SBP and hippocampal blood flow (ß=-1.55, P=0.03): Perfusion was the highest in subjects with mid-range SBP around 125 mm Hg. Longitudinally, in hypertensive subjects perfusion increased with increased SBP at low baseline SBP but increased with decreased SBP at high baseline SBP. Cortical and hippocampal perfusion decrease with increasing SBP across the entire BP spectrum. However, in hypertension, there seems to be a window of mid-range SBP which maximizes perfusion.

Effects of vascular risk factors, statins, and antihypertensive drugs on PiB deposition in cognitively normal subjects.

INTRODUCTION: Hypertension, hypercholesterolemia, and obesity increase the risk of dementia. Although their detection is commonly followed by an introduction of treatment, little is known about how medications frequently used to treat vascular risk affect amyloid deposition. METHODS: A cross-sectional study of 156 subjects who underwent positron emission tomography with PiB. Using linear regression, we tested whether blood pressure, cholesterol, overweight/obese status, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, angiotensin converting enzyme inhibitors, and statins predicted amyloid deposition. RESULTS: The use of ARBs (ß = -.15, P = .044) and diuretics (ß = -.20, P = .006) predicted less amyloid accumulation; older age (ß = .29, P < .001) and statins (ß = .23, P = .004) were related to greater amyloid deposition. Overweight and/or obese women had more cortical amyloid than their peers. DISCUSSION: Prospective studies should confirm effects of drugs and increased body weight on amyloid accumulation and establish whether they translate into measurable clinical outcomes. Women may be more susceptible to harmful effects of obesity.

Placing Evidence-Based Interventions at the Fingertips of School Social Workers.

Through a university-community collaborative partnership, the perceived needs of evidence-based practices (EBPs) among school social workers (SSWs) in a large school district in central Florida was assessed. A survey (response rate = 83.6%) found that although 70% of SSWs claim to use EBPs in their everyday practice, 40% do not know where to find them, which may partially explain why 78% of respondents claim to spend 1 to 4 h every week looking for adequate EBPs. From this needs assessment, the translational model was used to address these perceived needs. A systematic review of the literature found 40 tier 2 EBPs, most of which (23%) target substance use, abuse, and dependence. After discussion with academic and community partners, the stakeholders designed, discussed, and implemented a searchable, online, password-protected, interface of these tier 2 EBPs, named Evidence-Based Intervention Toolkit (eBIT). Lessons learned, future directions, and implications of this "one-stop shop" for behavioral health are discussed.

Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease.

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.

Reduced retention of Pittsburgh compound B in white matter lesions.

PURPOSE: One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging. METHODS: We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 ± 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted. RESULTS: PiB retention in WML was lower than in NAWM (p < 0.001, 14.6 % reduction). This was true both for periventricular WML (p < 0.001, 17.8 % reduction) and deep WML (p = 0.001, 7.5 % reduction). CONCLUSION: PiB binding in WM is influenced by the presence of WML, which lower the signal. Our findings add to the growing evidence that PiB can depict WM pathology and should prompt further investigations into PiB binding targets in WM.

Blood pressure decrease correlates with tau pathology and memory decline in hypertensive elderly.

In hypertension (HTN), cerebral blood flow regulation limits are changed, and the threshold for blood pressure (BP) at which perfusion is safely maintained is higher. This shift may increase the brain's vulnerability to lower BP in subjects with vascular disease. We investigated whether longitudinal reduction in mean arterial pressure (MAP) was related to changes in cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease in a group of cognitively healthy elderly with and without HTN. The relationships among MAP, memory decline, and hippocampal atrophy were also examined. Seventy-seven subjects (age 63.4 ± 9.4, range 44-86 years; education 16.9 ± 2.1, range 10-22 years; 60% women) were assessed twice, 2 ± 0.5 years apart. At both time points, all subjects underwent full medical and neuropsychological evaluations, lumbar punctures, and magnetic resonance imaging examinations. Twenty-five subjects had HTN. Hyper- and normotensive subjects did not differ in their CSF biomarkers, hippocampal volumes (HipVs), or memory scores at baseline. In the entire study group, the increase in tau phosphorylated at threonine 181 (p-tau(181)) was associated with a decline in verbal episodic memory (ß = -0.30, p = 0.01) and HipV reduction (ß = -0.27, p = 0.02). However, longitudinal decrease in MAP was related to memory decline (ß = 0.50, p = 0.01) and an increase in p-tau(181) (ß = -0.50, p = 0.01) only in subjects with HTN. Our findings suggest that the hypertensive group may be sensitive to BP reductions.

Cerebrospinal fluid biomarkers of Alzheimer's disease in healthy elderly.

Numerous studies have shown that Alzheimer's Disease (AD) pathology begins before the onset of clinical symptoms. Because therapies are likely to be more effective if they are implemented early in the disease progression, it is necessary to identify reliable biomarkers to detect AD pathology in the early stages of the disease, ideally in presymptomatic individuals. Recent research has identified three candidate cerebrospinal fluid (CSF) biomarkers that reflect AD pathology: amyloid beta, total tau protein (t-tau), and tau protein phosphorylated at AD-specific epitopes (p-tau). They are useful in supporting the AD diagnosis and have predictive value for AD when patients are in the stage of mild cognitive impairment (MCI). However, their predictive utility in cognitively healthy subjects is still being evaluated. We conducted a review of studies published between 1993 and 2011 and summarized their findings on the role of CSF biomarkers for AD in healthy elderly.

Cerebrovascular reactivity to carbon dioxide in Alzheimer's disease.

There is growing evidence that cerebrovascular reactivity to carbon dioxide (CVRCO2) is impaired in Alzheimer's disease (AD). Preclinical and animal studies suggest chronic hypercontractility in brain vessels in AD. We review (a) preclinical studies of mechanisms for impaired CVRCO2 in AD; (b) clinical studies of cerebrovascular function in subjects with AD dementia, mild cognitive impairment (MCI), and normal cognition. Although results of clinical studies are inconclusive, an increasing number of reports reveal an impairment of vascular reactivity to carbon dioxide in subjects with AD, and possibly also in MCI. Thus, CVRCO2 may be an attractive means to detect an early vascular dysfunction in subjects at risk.

Polo kinase and cytokinesis initiation in mammalian cells: harnessing the awesome power of chemical genetics.

The last decade has brought rapid advances in our knowledge of the human genome, as well as increasingly sophisticated methods to analyze how each of approximately 30,000 genes within it contribute to cellular, tissue, and organismal function. Here, we review this technological revolution in the context of Polo-like kinase 1 (Plk1), which has emerged as a central regulator of multiple processes fundamental to cell division. In particular, we highlight similarities and differences when Plk1 function is probed through various methods, including novel chemical inhibitors, and how our understanding of Plk1's role in mitosis and cell division has been enhanced as a consequence.

Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells.

Polo-like kinases (Plks) play crucial roles in mitosis and cell division. Whereas lower eukaryotes typically contain a single Plk, mammalian cells express several closely related but functionally distinct Plks. We describe here a chemical genetic system in which a single Plk family member, Plk1, can be inactivated with high selectivity and temporal resolution by using an allele-specific, small-molecule inhibitor, as well as the application of this system to dissect Plk1's role in cytokinesis. To do this, we disrupted both copies of the PLK1 locus in human cells through homologous recombination and then reconstituted Plk1 activity by using either the wild-type kinase (Plk1(wt)) or a mutant version whose catalytic pocket has been enlarged to accommodate bulky purine analogs (Plk1(as)). When cultured in the presence of these analogs, Plk1(as) cells accumulate in prometaphase with defects that parallel those found in PLK1(Delta/Delta) cells. In addition, acute treatment of Plk1(as) cells during anaphase prevents recruitment of both Plk1 itself and the Rho guanine nucleotide exchange factor (RhoGEF) Ect2 to the central spindle, abolishes RhoA GTPase localization to the equatorial cortex, and suppresses cleavage furrow formation and cell division. Our studies define and illuminate a late mitotic function of Plk1 that, although difficult or impossible to detect in Plk1-depleted cells, is readily revealed with chemical genetics.

Comparative study of the conditions required to image live human epithelial and fibroblast cells using atomic force microscopy.

Successful imaging of living human cells using atomic force microscopy (AFM) is influenced by many variables including cell culture conditions, cell morphology, surface topography, scan parameters, and cantilever choice. In this study, these variables were investigated while imaging two morphologically distinct human cell lines, namely LL24 (fibroblasts) and NCI H727 (epithelial) cells. The cell types used in this study were found to require different parameter settings to produce images showing the greatest detail. In contact mode, optimal loading forces ranged between 2-2.8 x 10(-9) and 0.1-0.7 x 10(-9) (N) for LL24 and NCI H727 cells respectively. In tapping (AC) mode, images of LL24 cells were obtained using cantilevers with a spring constant of at least 0.32 N/m, while NCI H727 cells required a greater spring constant of at least 0.58 N/m. To obtain tapping mode images, cantilevers needed to be tuned to resonate at higher frequencies than their resonance frequencies to obtain images. For NCI H727 cells, contact mode imaging produced the clearest images. For LL24 cells, contact and tapping mode AFM produced images of comparable quality. Overall, this study shows that cells with different morphologies and surface topography require different scanning approaches and optimal conditions must be determined empirically to achieve images of high quality.

Multiple roles for separase auto-cleavage during the G2/M transition.

The cysteine protease separase triggers anaphase onset by cleaving chromosome-bound cohesin. In humans, separase also cleaves itself at multiple sites, but the biological significance of this reaction has been elusive. Here we show that preventing separase auto-cleavage, via targeted mutagenesis of the endogenous hSeparase locus in somatic cells, interferes with entry into and progression through mitosis. The initial delay in mitotic entry was not dependent on the G2 DNA damage checkpoint, but rather involved improper stabilization of the mitosis-inhibiting kinase Wee1. During M phase, cells deficient in separase auto-cleavage exhibited striking defects in spindle assembly and metaphase chromosome alignment, revealing an additional early mitotic function for separase. Both the G2 and M phase phenotypes could be recapitulated by separase RNA interference and corrected by re-expressing wild-type separase in trans. We conclude that separase auto-cleavage coordinates multiple aspects of the G2/M programme in human cells, thus contributing to the timing and efficiency of chromosome segregation.