Objectives: MRI white matter hyperintensity (WMH) volume is associated with cognitive impairment. We hypothesized that specific loci of WMH would correlate with cognition even after accounting for total WMH volume.Methods: Subjects were identified from a prospective community-based study: 40 had normal cognition, 94 had mild impairment (defined here as a Clinical Dementia Rating [CDR] score of 0.5 without dementia), and 11 had mild Alzheimer's dementia. Factor analysis of a 22-item neuropsychological battery yielded 4 factors (episodic memory, executive function, spatial skills, and general knowledge). MRI WMH segmentation and analysis was performed using FreeSurfer software.Results: Higher WMH volume was independently associated with lower executive function and episodic memory factor scores. Voxel-based general linear models showed loci where WMH was strongly inversely associated with specific cognitive factor scores (p Ͻ 0.001), controlling for age, education, sex, APOE genotype, and total WMH volume. For episodic memory, clusters were observed in bilateral temporal-occipital and right parietal periventricular white matter, and the left anterior limb of the internal capsule. For executive function, clusters were observed in bilateral inferior frontal white matter, bilateral temporal-occipital and right parietal periventricular white matter, and the anterior limb of the internal capsule bilaterally.Conclusions: Specific WMH loci are closely associated with executive function and episodic memory, independent of total WMH volume. The anatomic locations suggest that WMH may cause cognitive impairment by affecting connections between cortex and subcortical structures, including the thalamus and striatum, or connections between the occipital lobe and frontal or parietal lobes. Neurology ® 2011;76:1492-1499 GLOSSARY AD ϭ Alzheimer disease; CADASIL ϭ cerebral autosomal dominant arteriopathy with stroke and ischemic leukoencephalopathy; CDR ϭ Clinical Dementia Rating; DSM-IV ϭ Diagnostic and Statistical Manual of Mental Disorders, 4th edition; FA ϭ fractional anisotropy; MCI ϭ mild cognitive impairment; PDW ϭ proton density-weighted; SPGR ϭ spoiled gradient recalled; T1W ϭ T1-weighted; T2W ϭ T2-weighted; TE ϭ echo time; TR ϭ repetition time; WMH ϭ white matter hyperintensity.There is growing recognition that ischemic brain lesions are a significant contributor to cognitive impairment and that many cases of dementia are mixed, with a cerebrovascular component.1 Ischemic white matter lesions, seen on MRI as white matter hyperintensity (WMH), have previously been associated with decreased performance on neuropsychological testing, 2,3 and risk of mild cognitive impairment 4 and dementia. 5 It has been hypothesized that WMH interfere with cognitive processing by impairing the speed or fidelity of signal transmission through affected areas. 6 The direct evidence to support this hypothesis is scant, however. 6We reasoned that if WMH impair white matter function, then clinical impairments should be associated with WM...

Background and Purpose-We investigated the sensitivity and reliability of MRI susceptibility-weighted imaging (SWI) compared with routine MRI T2*-weighted gradient-recalled echo (GRE) for cerebral microbleed (CMB) detection. Methods-We used data from a prospective study of cerebral amyloid angiopathy (n=9; mean age, 71±8.3) and healthy non-cerebral amyloid angiopathy controls (n=22; mean age, 68±6.3). Three raters (labeled 1, 2, and 3) independently interpreted the GRE and SWI sequences (using the phase-filtered magnitude image) blinded to clinical information. Results-In 9 cerebral amyloid angiopathy cases, the raters identified 1146 total CMBs on GRE and 1432 CMBs on SWI.In 22 healthy control subjects, the raters identified ≥1 CMBs in 6/22 on GRE (total 9 CMBs) and 5/22 on SWI (total 19 CMBs). Among cerebral amyloid angiopathy cases, the reliability between raters for CMB counts was good for SWI (intraclass correlation coefficient, 0.87) but only moderate for GRE (intraclass correlation coefficient, 0.52). In controls, agreement on the presence or absence of CMBs in controls was moderate to good on both SWI (κ coefficient ranged from 0.57 to 0.74 across the 3 combinations of rater pairs) and GRE (κ range, 0.31 to 0.70). A review of 114 hypointensities identified as possible CMBs indicated that increased detection and reliability on SWI was related to both increased contrast and higher resolution, allowing better discrimination of CMBs from the background and better anatomic differentiation from pial vessels. Conclusions-SWI confers greater reliability as well as greater sensitivity for CMB detection compared with GRE, and should be the preferred sequence for quantifying CMB counts. (Stroke. 2013;44:2782-2786.)

The purpose of this study is to directly compare the dynamic responses of phosphocreatine (PCr) and P(i) to those oxygen uptake (VO2) measured at the lung during transitions to and from moderate-intensity exercise. Changes in PCr and P(i) were measured by 31P-nuclear magnetic resonance spectroscopy, and changes in VO2 were measured breath by breath by mass spectroscopy during transitions to and from moderate-intensity square-wave ankle plantar flexion exercise in 11 subjects (7 men and 4 women; mean age 27 yr). Three repeated transitions were averaged for improvement in signal-to-noise ratio of phosphate data, and 12 transitions were averaged for VO2 measurements. Averaged transitions were fit with a monoexponential curve for determination of the time constant (tau) of the responses. Mean tau values for on transients of PCr, P(i), and phrase 2 VO2 were 47.0, 57.7, and 44.5 s, respectively, whereas means tau values for off transients were 44.8, 42.1, and 33.4 s, respectively. There were no significant differences between tau values for phosphate- and VO2-measured transients or on and off transients. The similarity of on and off kinetics supports linear first-order respiratory control models. Measurement of phase 2 pulmonary VO2 kinetics to and from moderate-intensity small-muscle-mass exercise reflect muscle phosphate kinetics (and muscle oxygen consumption).

Objectives: We used functional MRI (fMRI), transcranial Doppler ultrasound, and visual evoked potentials (VEPs) to determine the nature of blood flow responses to functional brain activity and carbon dioxide (CO 2 ) inhalation in patients with cerebral amyloid angiopathy (CAA), and their association with markers of CAA severity.Methods: In a cross-sectional prospective cohort study, fMRI, transcranial Doppler ultrasound CO 2 reactivity, and VEP data were compared between 18 patients with probable CAA (by Boston criteria) and 18 healthy controls, matched by sex and age. Functional MRI consisted of a visual task (viewing an alternating checkerboard pattern) and a motor task (tapping the fingers of the dominant hand).Results: Patients with CAA had lower amplitude of the fMRI response in visual cortex compared with controls (p 5 0.01), but not in motor cortex (p 5 0.22). In patients with CAA, lower visual cortex fMRI amplitude correlated with higher white matter lesion volume (r 5 20.66, p 5 0.003) and more microbleeds (r 5 20.78, p , 0.001). VEP P100 amplitudes, however, did not differ between CAA and controls (p 5 0.45). There were trends toward reduced CO 2 reactivity in the middle cerebral artery (p 5 0.10) and posterior cerebral artery (p 5 0.08).Conclusions: Impaired blood flow responses in CAA are more evident using a task to activate the occipital lobe than the frontal lobe, consistent with the gradient of increasing vascular amyloid severity from frontal to occipital lobe seen in pathologic studies. Reduced fMRI responses in CAA are caused, at least partly, by impaired vascular reactivity, and are strongly correlated with other neuroimaging markers of CAA severity. Neurology ® 2013;81:1659-1665 GLOSSARY BOLD 5 blood oxygen level-dependent; CAA 5 cerebral amyloid angiopathy; CO 2 5 carbon dioxide; DEF 5 dynamic end-tidal forcing; DSM-IV 5 Diagnostic and Statistical Manual of Mental Disorders, 4th edition; fMRI 5 functional MRI; ICH 5 intracerebral hemorrhage; PETCO 2 5 partial pressure of end-tidal carbon dioxide; VEP 5 visual evoked potential; WMH 5 white matter hyperintensity.Cerebral amyloid angiopathy (CAA) is best recognized clinically as a cause of frequent recurrent intracerebral hemorrhages (ICHs) and microbleeds, reflecting loss of vascular integrity due to b-amyloid deposition.1 However, accumulating evidence suggests that impaired vascular reactivity is another feature of CAA. In a mouse model of severe CAA, there was decreased vasodilation in response to whisker barrel stimulation and to carbon dioxide (CO 2 ) inhalation, a vasodilatory stimulus.2 In a small study of patients with probable CAA, posterior cerebral artery flow velocity responses were lower than controls when viewing a visual stimulus, but middle cerebral artery flow velocity responses to CO 2 inhalation were relatively preserved.3 It was not clear whether the differential responses observed in the visual and CO 2 experiments were due to the different arteries tested, the different types of vasodilatory stimulus used, or wer...

ObjectiveDecline in cognitive function begins by the 40s, and may be related to future dementia risk. We used data from a community-representative study to determine whether there are age-related differences in simple cognitive and gait tests by the 40s, and whether these differences were associated with covert cerebrovascular disease on magnetic resonance imaging (MRI).MethodsBetween 2010 and 2012, 803 participants aged 40 to 75 years in the Prospective Urban Rural Epidemiological (PURE) study, recruited from prespecified postal code regions centered on 4 Canadian cities, underwent brain MRI and simple tests of cognition and gait as part of a substudy (PURE-MIND).ResultsMean age was 58 ± 8 years. Linear decreases in performance on the Montreal Cognitive Assessment, Digit Symbol Substitution Test (DSST), and Timed Up and Go test of gait were seen with each age decade from the 40s to the 70s. Silent brain infarcts were observed in 3% of 40- to 49-year-olds, with increasing prevalence up to 18.9% in 70-year-olds. Silent brain infarcts were associated with slower timed gait and lower volume of supratentorial white matter. Higher volume of supratentorial MRI white matter hyperintensity was associated with slower timed gait and worse performance on DSST, and lower volumes of the supratentorial cortex and white matter, and cerebellum.InterpretationCovert cerebrovascular disease and its consequences on cognitive and gait performance and brain atrophy are manifest in some clinically asymptomatic persons as early as the 5th decade of life. Ann Neurol 2015;77:251–261

Introduction Many consequences of cerebrovascular disease are identifiable by magnetic resonance imaging (MRI), but variation in methods limits multicenter studies and pooling of data. The European Union Joint Program on Neurodegenerative Diseases (EU JPND) funded the HARmoNizing Brain Imaging MEthodS for VaScular Contributions to Neurodegeneration (HARNESS) initiative, with a focus on cerebral small vessel disease. Methods Surveys, teleconferences, and an in-person workshop were used to identify gaps in knowledge and to develop tools for harmonizing imaging and analysis. Results A framework for neuroimaging biomarker development was developed based on validating repeatability and reproducibility, biological principles, and feasibility of implementation. The status of current MRI biomarkers was reviewed. A website was created at www.harness-neuroimaging.org with acquisition protocols, a software database, rating scales and case report forms, and a deidentified MRI repository. Conclusions The HARNESS initiative provides resources to reduce variability in measurement in MRI studies of cerebral small vessel disease.

The septins were first discovered in the budding yeast Saccharomyces cerevisiae and were named for their role in cytokinesis and septum formation (69). Septins are now known to be highly conserved in fungi and animals, although absent in plants and many protozoans (e.g., Plasmodium fasciculatum and Dictyostelium discoideum). The septin proteins are characterized by presence of a distinct type of GTPase domain and by their ability to form filaments. The S. cerevisiae septin proteins form a series of 10-nm filaments that assemble into a ring on the inner surface of the plasma membrane at the bud neck. Septin rings are thought to function as a scaffold to recruit proteins to the bud neck and to act as a boundary domain to restrict diffusion during budding and cytokinesis (30,39,66,68). However, septins are now implicated in a broad range of dynamic membrane events. In S. cerevisiae, septins have been found to also play a role in conjugation and sporulation. Moreover, analyses of septin function in other organisms, including fungi that undergo different patterns of growth and differentiation, are revealing new aspects of septin function. Therefore, we will provide an overview of the current understanding of the relatively well-studied roles of septins during S. cerevisiae budding and then use this as a context to review studies of septin function during other developmental pathways in S. cerevisiae and other fungi. The other fungi will include the model fission yeast Schizosaccharomyces pombe and two opportunistic fungal pathogens: the multimorphic Candida albicans and the filamentous fungus Aspergillus nidulans.

No abstract