High-Frequency Transient Elastography Prototype to Assess Skin (Dermis) Fibrosis: A Diagnostic Study in Patients with Venous Insufficiency and Controls.

PURPOSE: High-frequency transient elastography (HF-TE) is a noninvasive technique for assessing shear-wave speed and finally elasticity in thin tissue such as the skin. It has never been validated for monitoring fibrotic skin diseases. The purpose was to evaluate the potential of HF-TE to assess skin fibrosis in patients with chronic venous disorders (CVD). MATERIALS AND METHODS: This clinical study enrolled 48 patients at various stages of CVD and 48 paired healthy volunteers. Subjects underwent a clinical examination with an evaluation of Rodnan's fibrosis skin score. We studied the dermis thickness measured using ultrasound (US) and elasticity measurements using cutometer and HF-TE studied according to 3 cutaneous zones positioned on the leg. The area under the receiver operating characteristic curve (AUC) was calculated to evaluate the diagnosis performance for a combined parameter (PRL) based on a logistic regression model using both elasticity and dermal thickness. RESULTS: Patients with CVD had significantly higher values of skin elasticity than healthy subjects, 134.5 kPa and 132.1 kPa vs. 91.3 kPa, respectively. The dermis thickness also increased with escalation in CVD stage for all studied zones. The PRL parameter had an AUC value of 0.79 for all zones and stages of CVD clustered. The discriminating power of PRL increased with escalation of the CVD stage; with an AUC value of up to 0.89 for evolved stages, and a sensitivity and specificity of 0.79 and 0.89, respectively. CONCLUSION: HF-TE, coupled with a US measurement of dermis thickness, made it possible to propose a new biomarker, which proved to be a good diagnostic tool for skin fibrosis.

Amyloid PET Positivity in Different Primary Progressive Aphasia Phenotypes.

PURPOSE: Primary progressive aphasia (PPA) is a neurological syndrome in which language functions become progressively impaired with relative sparing of memory and other instrumental functions. The pathologic causes of PPA are heterogeneous, but studies suggest that logopenic PPA (LPA) is underpinned by Alzheimer disease (AD) pathology in a high proportion of cases. The purposes of this descriptive and retrospective study were to characterize F-florbetapir PET imaging in a group of patients with a clinical syndrome of PPA, to determine the value of clinical characterization based on language phenotype in predicting the underlying pathology of PPA with F-florbetapir, and to quantify amyloid load in PPA subjects classified as "positive" F-florbetapir scans. Then, we compare the quantification and distribution of F-florbetapir uptake with those of typical, predominantly amnestic AD patients. METHODS: We conducted a PET study with F-florbetapir in a cohort of 12 right-handed patients diagnosed with PPA: 3 patients with semantic-variant PPA, 5 with nonfluent PPA, 1 with LPA, and 3 unclassifiable patients. We evaluated amyloid deposition between APP groups and 11 patients with typical amnestic AD. RESULTS: Among the 12 patients with PPA syndrome, 8 (66.7%) were considered as amyloid positive. One of the 3 patients with semantic-variant PPA was F-florbetapir positive. In contrast, 4 of the 5 nonfluent-variant PPA, 2 of the 3 unclassifiable cases and the single patient with LPA were F-florbetapir positive. A significantly higher F-florbetapir uptake was observed in PPA F-florbetapir-positive patients compared with typical AD patients. This difference was observed in all regions of interest, except in posterior cingulate and temporal cortex. CONCLUSIONS: These results suggest that F-florbetapir PET may be useful in a routine clinical procedure to improve the reliability of identifying AD pathology in patients with PPA syndrome, with different clinical subtypes of the PPA syndrome.

Brain Tissue Pulsatility is Increased in Midlife Depression: a Comparative Study Using Ultrasound Tissue Pulsatility Imaging.

Cerebrovascular disease (CVD) is consistently associated with late-life depression but poorly documented in midlife depression. It can be hypothesized that the relatively low sensitivity of conventional neuroimaging techniques does not allow the detection of subtle CVD in midlife depression. We used tissue pulsatility imaging (TPI), a novel ultrasound (US) neuroimaging technique that has demonstrated good sensitivity to detect changes in the pulsatility of small brain volumes, to identify early and subtle changes in brain vascular function in midlife depression. We compared the maximum and mean brain tissue pulsatility (MaxBTP and MeanBTP), as identified by TPI, between three groups of middle-aged females matched for age: patients with depression (n=25), patients with remitted depression (n=24) and community controls (n=25). MRI arterial spin labeling, white matter hyperintensities (WMHs) and transcranial doppler (TCD) were used as control conventional markers for CVD. We found no difference in the MRI and TCD measures among the three groups. In contrast, depressive patients showed an increased BTP related to the mean global brain pulsatility (MeanBTP) and no change related to large vessels (MaxBTP) in comparison with the remitted and control groups. US neuroimaging is a highly accurate method to detect brain pulsatility changes related to cerebrovascular functioning, and TPI identified an increased BTP in midlife depressed patients, suggesting early and subtle vascular impairments in this population at risk for CVD such as stroke or WMHs. Because high pulsatility could represent prodromal cerebrovascular changes that damage the brain over time, this paper provides a potential target for blocking the progression of CVD.

Ultrasound Tissue Pulsatility Imaging Suggests Impairment in Global Brain Pulsatility and Small Vessels in Elderly Patients with Orthostatic Hypotension.

BACKGROUND: Orthostatic hypotension (OH) is highly prevalent in the elderly, and this population can be exposed to serious complications, including falls and cognitive disorders, as well as overall mortality. However, the pathophysiology of OH is still poorly understood, and innovative methods of cerebral blood flow (CBF) assessment have been required to accurately investigate cerebrovascular reactivity in OH. OBJECTIVES: We want to compare brain tissue pulsatility (BTP) changes during an orthostatic challenge in elderly patients over 80 with and without OH. MATERIALS AND METHODS: Forty-two subjects aged 80 and over were recruited from the geriatric unit of the Hospital of Tours, France, and were divided into two groups according to the result of an orthostatic challenge. The noninclusion criteria were any general unstable medical condition incompatible with orthostatic challenge, having no temporal acoustic window, severe cognitive impairment (Mini Mental Status Examination <15), history of stroke, and legal guardianship. We used the novel and highly sensitive ultrasound technique of tissue pulsatility imaging to measure BTP changes in elderly patients with (n = 22) and without OH (n = 17) during an orthostatic challenge. RESULTS: We found that the mean brain tissue pulsatility related to global intracranial pulsatility, but not maximum brain tissue pulsatility related to large arteries pulsatility, decreased significantly in OH patients, with a delay compared with the immediate drop in peripheral blood pressure. CONCLUSION: Global pulsatile CBF changes and small vessels pulsatility, rather than changes in only large arteries, may be key mechanisms in OH to account for the links between OH and cerebrovascular disorders.

Precuneus and Cingulate Cortex Atrophy and Hypometabolism in Patients with Alzheimer's Disease and Mild Cognitive Impairment: MRI and (18)F-FDG PET Quantitative Analysis Using FreeSurfer.

OBJECTIVE: The objective of this study was to compare glucose metabolism and atrophy, in the precuneus and cingulate cortex, in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI), using FreeSurfer. METHODS: 47 individuals (17 patients with AD, 17 patients with amnestic MCI, and 13 healthy controls (HC)) were included. MRI and PET images using (18)F-FDG (mean injected dose of 185 MBq) were acquired and analyzed using FreeSurfer to define regions of interest in the hippocampus, amygdala, precuneus, and anterior and posterior cingulate cortex. Regional volumes were generated. PET images were registered to the T1-weighted MRI images and regional uptake normalized by cerebellum uptake (SUVr) was measured. RESULTS: Mean posterior cingulate volume was reduced in MCI and AD. SUVr were different between the three groups: mean precuneus SUVr was 1.02 for AD, 1.09 for MCI, and 1.26 for controls (p < 0.05); mean posterior cingulate SUVr was 0.96, 1.06, and 1.22 for AD, MCI, and controls, respectively (p < 0.05). CONCLUSION: We found graduated hypometabolism in the posterior cingulate cortex and the precuneus in prodromal AD (MCI) and AD, whereas atrophy was not significant. This suggests that the use of (18)F-FDG in these two regions could be a neurodegenerative biomarker.

The Pattern of Brain Amyloid Load in Posterior Cortical Atrophy Using (18)F-AV45: Is Amyloid the Principal Actor in the Disease?

BACKGROUND: Posterior cortical atrophy (PCA) is characterized by progressive higher-order visuoperceptual dysfunction and praxis declines. This syndrome is related to a number of underlying diseases, including, in most cases, Alzheimer's disease (AD). The aim of this study was to compare the amyloid load with (18)F-AV45 positron emission tomography (PET) between PCA and AD subjects. METHODS: We performed (18)F-AV45 PET, cerebrospinal fluid (CSF) biomarker analysis and a neuropsychological assessment in 11 PCA patients and 12 AD patients. RESULTS: The global and regional (18)F-AV45 uptake was similar in the PCA and AD groups. No significant correlation was observed between global (18)F-AV45 uptake and CSF biomarkers or between regional (18)F-AV45 uptake and cognitive and affective symptoms. CONCLUSION: This (18)F-AV45 PET amyloid imaging study showed no specific regional pattern of cortical (18)F-AV45 binding in PCA patients. These results confirm that a distinct clinical phenotype in amnestic AD and PCA is not related to amyloid distribution.

The effect of age and educational level on the cognitive processes used to comprehend the meaning of pictograms.

BACKGROUND AND AIMS: Pictograms, designed to be a universal communication system, are often created from several concrete and easily recognizable drawings. Does understanding depend on a logical approach? Or is it the ability to inhibit the concrete sense of each picture that allows access to a higher level of comprehension? (ability to abstract). These executive functions are sensitive to the effects of aging and educational level. The aim of our study was to evaluate the nature of the cognitive processes underlying the meaning of pictograms and to test the effect of aging and educational level. METHODS: We enrolled 19 older adults (60-69 years old) and 63 young adults (20-29 years old). Of these 63 young adults, 43 had a high educational level (Young-High participants), and 20 had a lower educational level (Young-Low participants). Each participant was asked the meaning of 20 pictograms and underwent an assessment of abstraction and logical abilities with WAIS-III test. RESULTS: Older adults had lower pictogram assessment scores and abstraction and logical abilities when compared with young adults. In both groups, abstraction and logical abilities were correlated with the interpretation of pictograms but only abstraction ability remains strongly correlated with pictogram comprehension in the older group after adjustment of sex, age and educational level. Consequently, the poorer performances of older adults to determine the meaning of pictograms could be explained by the decline of abstraction ability in elderly. CONCLUSIONS: Pictograms are not the universal communication system as we formerly thought. Age and educational level may influence the performance in determining the meaning of pictograms.

Brain [18F]FDDNP binding and glucose metabolism in advanced elderly healthy subjects and Alzheimer's disease patients.

BACKGROUND: Positron emission tomography (PET) imaging of brain amyloid (Aß) and neurofibrillary tangle (NFT) load is a candidate biomarker of Alzheimer's disease (AD). OBJECTIVES: To compare brain Aß and NFT load and glucose metabolism in advanced elderly (70 years and older) patients with AD and healthy controls (HCs) by PET with [18F]FDDNP and [18F]FDG. METHODS: Seven AD patients (mean ± SD age 79.3 ± 3.6 y, Mini-Mental State Examination (MMSE) score 22.1 ± 2.5) and eight HCs (mean age ± SD, 75.7 ± 3.9 y; MMSE score 29.0 ± 1.2) underwent PET with [18F]FDDNP and [18F]FDG. RESULTS: Global [18F]FDDNP uptake was significantly higher (p < 0.05) in AD patients (1.15 ± 0.04) than in HCs (1.10 ± 0.06), while global brain metabolism was lower in AD patients than in HCs (AD patients 0.96 ± 0.09; HCs 1.13 ± 0.11; p < 0.05). In HCs, brain glucose metabolism was correlated with age for both the global [18F]FDG SUVr and in the parietal and posterior cingulate regions, while no correlation was found between age and [18F]FDDNP uptake. In AD patients, global [18F]FDDNP uptake and uptake in the frontal and anterior cingulate regions of interest were correlated with MMSE score, while no correlation was observed with brain glucose metabolism. CONCLUSION: Imaging Aß load and NFT with [18F]FDDNP can distinguish AD patients from HCs in an advanced elderly population. It seems to be less sensitive than [18F]FDG to the brain changes observed with normal aging, but more sensitive to cognitive decline in advanced elderly AD patients.

Longitudinal and parallel monitoring of neuroinflammation and neurodegeneration in a 6-hydroxydopamine rat model of Parkinson's disease.

As neuroinflammatory processes are involved in the pathogenesis of Parkinson's disease (PD), we achieved the longitudinal evaluation of them in parallel with the modifications of dopaminergic function at several time-points after 6-hydroxydopamine (6-OHDA) lesion in the rat mimicking an early stage of PD. After unilateral intrastriatal 6-OHDA administration, we quantified the temporal evolution of the 18 kDa translocator protein (TSPO), TH-immunoreactivity and dopamine transporters in the striatum and substantia nigra pars compacta (SNc) from 3- to 56-days postlesion (dpl). Increased binding of TSPO ligands used, i.e., [(3)H]PK11195 and [(125)I]CLINDE, was observed in the lesioned striatum at 3, 7, and 14 dpl, followed by a progressive return to the basal level at 56 dpl. The binding profile in the SNc showed progressive binding beginning at 3 dpl, peaking at 14 dpl, and progressively decreasing until 56 dpl. In this model, the neuroinflammatory and neurodegenerative processes occurred concomitantly. The transitory occurrence of microglial activation could be involved in the lasting installation of dopaminergic neuron loss.

Tolerance of low-frequency ultrasound sonophoresis: a double-blind randomized study on humans.

BACKGROUND: Sonophoresis [low-frequency ultrasound (US)] has been used in animals and in vitro to investigate enhanced percutaneous absorption of drugs. No study focused on its clinical human tolerance has been published as yet. METHODS: We aimed to assess the bioeffects of low-frequency US in vivo on human skin in a double-blind randomized-controlled study. We applied pulse-mode US at 36 kHz for 5 min in a step procedure of increasing dosage, from 1.57 to 3.50 W/cm(2), and placebo. The primary outcome was toxic effects of the procedure, defined as a pain score >40 on a 0-100 mm visual analogue scale or necrosis. Erythema (scored from 0 to 3 in severity) was also evaluated. The secondary outcomes were measurements of skin thickness by high-resolution skin imaging, of skin capacitance and temperature. RESULTS: We included 34 healthy volunteers. We found no pain score >38 and no skin necrosis with either US or placebo. Erythema was systematically observed immediately after US application, but after 1 day, we observed three cases in the knee group. The most frequent adverse effect was tinnitus. We observed no marked increase in temperature or cutaneous thickness after US or placebo. Cutaneous capacitance increased immediately after both applications. CONCLUSION: Such data demonstrating good tolerance of sonophoresis can be useful before the initiation of a clinical trial of the therapeutic use of low-frequency sonophoresis in humans.

Efficiency of low-frequency ultrasound sonophoresis in skin penetration of histamine: a randomized study in humans.

Low-frequency ultrasound (US) applied to skin (sonophoresis) has been investigated to enhance the transdermal transport of various drugs. Histamine is usually used in allergy investigations. We aimed to investigate, in a randomized study, the transdermal penetration of histamine with sonophoresis. Ten subjects were included. Their right forearm was divided into three zones, which were randomly assigned a treatment: no US, US(1) (I(1)=2.72 W/cm(2)), US(2) (I(2)=3.50 W/cm(2)). The primary outcome was area of induced papule, which revealed histamine penetration. Secondary outcomes were echographic measurement of papule (skin thickness) and pruritus. Measurements were taken immediately after US application and after 30 min, 2 h and 24 h. Arm zones without US application showed no papules induced by histamine; 9/10 subjects receiving US showed papules. Their mean size increased with increased intensity of US but not significantly. The skin thickness increased with US. Pruritus occurred in 7/10 cases after US and histamine. The adverse events were skin erythema, pain and tinnitus. Though this study included a few number of patients, it confirms that sonophoresis enhances skin penetration of histamine. This technology could be used at therapeutic levels: histamine could be used with sonophoresis as a positive control in allergy testing instead of prick tests, which involve skin disruption with a lancet.

Conversion from nonischemic to ischemic retinal vein occlusion: prediction by venous velocity on color Doppler imaging.

PURPOSE: To identify color Doppler imaging (CDI) parameters and other prognostic factors of a conversion from nonischemic to ischemic retinal vein occlusion (RVO) in a large population with a long follow-up. METHODS: This was a retrospective observational study. Data were collected for patients who had been admitted to the ophthalmologic department of the Hospital of Tours because of nonischemic central RVO (CRVO) or branch RVO (BRVO). We analyzed the relation between time until conversion into ischemic RVO and several prognostic factors of conversion, mainly vein velocities as measured by CDI. RESULTS: Analyses involved 162 patients. One year after inclusion, conversion into ischemic RVO occurred in 25.0% of the 113 CRVO and in 28.6% of the 49 BRVO cases. For CRVO, an increase of the minimal central retinal venous velocity (CRV), measured by CDI before and after treatment by hemodilution, diminished the risk of conversion into an ischemic form (p=0.048). For BRVO, an elevated maximal CRV on diagnosis was a protector (p=0.004). Age was associated with a high risk of ischemic evolution for CRVO (p=0.023) but not BRVO. Initial visual acuity was not associated with the conversion, for BRVO or CRVO. Increased retinal hemorrhages highly increased the risk of conversion both for CRVO (p<0.0001) and BRVO (p=0.010). CONCLUSIONS: Risk of ischemic evolution for BRVO and CRVO treated by isovolemic hemodilution was associated with central venous velocities. CDI might be useful for identifying risk of ischemic conversion and individualizing the follow-up of patients.

Design effect in multicenter studies: gain or loss of power?

BACKGROUND: In a multicenter trial, responses for subjects belonging to a common center are correlated. Such a clustering is usually assessed through the design effect, defined as a ratio of two variances. The aim of this work was to describe and understand situations where the design effect involves a gain or a loss of power. METHODS: We developed a design effect formula for a multicenter study aimed at testing the effect of a binary factor (which thus defines two groups) on a continuous outcome, and explored this design effect for several designs (from individually stratified randomized trials to cluster randomized trials, and for other designs such as matched pair designs or observational multicenter studies). RESULTS: The design effect depends on the intraclass correlation coefficient (ICC) (which assesses the correlation between data for two subjects from the same center) but also on a statistic S, which quantifies the heterogeneity of the group distributions among centers (thus the level of association between the binary factor and the center) and on the degree of global imbalance (the number of subjects are then different) between the two groups. This design effect may induce either a loss or a gain in power, depending on whether the S statistic is respectively higher or lower than 1. CONCLUSION: We provided a global design effect formula applying for any multicenter study and allowing identifying factors - the ICC and the distribution of the group proportions among centers - that are associated with a gain or a loss of power in such studies.

Center effect on ankle-brachial index measurement when using the reference method (Doppler and manometer): results from a large cohort study.

BACKGROUND: The ankle-brachial index (ABI) is a simple and noninvasive tool used to detect peripheral arterial disease (PAD). We aimed to assess, in a French multicenter cohort, the center effect associated with arterial pressure (AP) and ABI measurements using the reference method and using a semiautomatic device. METHODS: This study included baseline and 9-year follow-up data from 3,664 volunteers of 10 health examination centers of the DESIR (Data from an Epidemiological Study on the Insulin Resistance) syndrome French cohort. Ankle and brachial AP were measured at inclusion by the reference method (a mercury sphygmomanometer coupled with a Doppler probe for ankle measurements) and at 9 years by a semiautomatic device (Omron HEM-705CP). The center effect was assessed by the intraclass correlation coefficient (ICC), ratio of the between-center variance to the total variance of the measurement. RESULTS: At inclusion, the sample mean age was 47.5 (s.d. 9.9) years; 49.3% were men. Although ICCs were smaller than 0.05 for brachial AP measurements, they were close to 0.18 and 0.20 for ankle systolic AP (SAP) and ABI measurements, respectively, when the reference method was used. No center effect for measures other than ankle SAP was detected. With the semiautomatic device method, all ICCs, including those for ankle SAP and ABI measurements, were between 0.005 and 0.04. CONCLUSIONS: We found an important center effect on ABI measured with a sphygmomanometer and a Doppler probe but not a semiautomatic device. A center effect should be taken into account when planning any multicenter study on ABI measurement.

Sample size calculation for multicenter randomized trial: taking the center effect into account.

In multicenter trials, data from the same center are more similar than those from different centers. These similarities induce a correlation between data, known as the center effect, which is assessed by the intraclass correlation coefficient (ICC). Here, we derive a sample size formula for continuous data that takes into account this center effect. Our analytical developments lead to an elementary formula different from the classical one by a (1-rho) factor, where rho is the ICC. This work allows for adjusting and reducing the sample size according to the magnitude of the center effect and leads to a better consistency in the conduct of multicenter randomized trials.

The impact of 3-year changes in lifestyle habits on metabolic syndrome parameters: the D.E.S.I.R study.

BACKGROUND: The effect of lifestyle changes in cohorts of free-living populations has been surprisingly little evaluated. DESIGN: A longitudinal study. METHODS: In the French Data from an Epidemiological Study on the Insulin Resistance (D.E.S.I.R) study of 1958 men and 2028 women, aged 30-65 years, the impact of 3-year changes in lifestyle habits (sporting activity, physical activity at home and at work, alcohol drinking, smoking) on metabolic syndrome parameters [insulin, glucose, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic blood pressure, waist circumference] and on body mass index (BMI) were investigated. RESULTS: In men, 3-year increases in sporting activity were associated with a lowering of insulin, glucose, systolic blood pressure and waist circumference (all P < 0.05). For women, the only effect was on lowering waist circumference (P < 0.03). Increases in physical activity at home were beneficially associated with HDL-cholesterol, triglycerides, waist circumference and BMI changes (all P < 0.05) in men, but had no apparent effect in women. Decreases in alcohol intake only had an effect in men, with decreases in HDL-cholesterol and systolic blood pressure (P < 0.05), whereas decreasing cigarette smoking in men was associated with significant increases in insulin, glucose, triglycerides, waist and BMI (P < 0.001), and in women HDL-cholesterol, waist circumference and BMI increased (P < 0.02). These results were mainly caused by those who had stopped smoking. CONCLUSIONS: Increases in physical activity over the 3-year period were associated with beneficial effects on syndrome parameters, particularly in men. Smoking cessation and alcohol moderation produced mixed effects on these parameters.