François Herrmann

Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease

Objective: To examine the relationship between stereologic estimates of AD-related pathology and severity of cognitive deficits in brain aging. Background: Previous studies reported substantial contributions of neurofibrillary tangles (NFT), amyloid deposits, and neuronal loss to the development of dementia. However, the prediction of cognitive status based on nonstereologic quantification of these measures has led to conflicting results. Such studies have measured densities, rather than absolute numbers, and most do not take into account the potential interaction between the above pathologic hallmarks in a global multivariate analysis. Methods: Clinicopathologic study in 22 elderly cases. Cognitive status assessed prospectively using the Mini-Mental State Examination (MMSE); stereologic assessment of NFT, unaffected neurons, and total amyloid volume in the CA1 field of the hippocampus, entorhinal cortex, and area 9. Statistical analysis was performed using both univariate and multivariate linear regression models. Results: High total NFT counts but not amyloid volume were strongly associated with a lower number of unaffected neurons in all areas studied. A high proportion of variability in MMSE scores was explained by NFT and neuronal counts in the CA1 field (83% and 85.4%), entorhinal cortex (87.8% and 83.7%), and area 9 (87% and 79%); amyloid volume in the entorhinal cortex, but not in the CA1 field and area 9, accounted for 58.5% of MMSE variability. Multivariate analyses showed that total NFT counts in the entorhinal cortex and area 9 as well as neuron numbers in the CA1 field were the best predictors of MMSE score. Conclusions: These new stereologic data indicate that neuronal pathology in hippocampal formation and frontal cortex closely reflects the progression of cognitive deficits in brain aging and AD. They also demonstrate that amyloid volume has no additional predictive value, in terms of clinicopathologic correlations, beyond its interaction with NFT.

Death toll exceeded 70,000 in Europe during the summer of 2003

Daily numbers of deaths at a regional level were collected in 16 European countries. Summer mortality was analyzed for the reference period 1998-2002 and for 2003. More than 70,000 additional deaths occurred in Europe during the summer 2003. Major distortions occurred in the age distribution of the deaths, but no harvesting effect was observed in the months following August 2003. Global warming constitutes a new health threat in an aged Europe that may be difficult to detect at the country level, depending on its size. Centralizing the count of daily deaths on an operational geographical scale constitutes a priority for Public Health in Europe.

Stops walking when talking: a predictor of falls in older adults?

The objective of this study was to systematically review all published articles examining the relationship between the occurrence of falls and changes in gait and attention‐demanding task performance whilst dual tasking amongst older adults. An English and French Medline and Cochrane library search ranging from 1997 to 2008 indexed under ‘accidental falls’, ‘aged OR aged, 80 and over’, ‘dual task’, ‘dual tasking’, ‘gait’, ‘walking’, ‘fall’ and ‘falling’ was performed. Of 121 selected studies, fifteen met the selection criteria and were included in the final analysis. The fall rate ranged from 11.1% to 50.0% in retrospective studies and from 21.3% to 42.3% in prospective ones. Amongst the three retrospective and eight prospective studies, two and six studies, respectively, showed a significant relationship between changes in gait performance under dual task and history of falls. The predictive value for falling was particularly efficient amongst frail older adults compared with healthy subjects. Two prospective studies challenged the usefulness of the dual‐task paradigm as a significant predictor compared to single task performance and three studies even reported that gait changes whilst dual tasking did not predict falls. The pooled odds ratio for falling was 5.3 (95% CI, 3.1–9.1) when subjects had changes in gait or attention‐demanding task performance whilst dual tasking. Despite conflicting early reports, changes in performance whilst dual tasking were significantly associated with an increased risk for falling amongst older adults and frail older adults in particular. Description of health status, standardization of test methodology, increase of sample size and longer follow‐up intervals will certainly improve the predictive value of dual‐task‐based fall risk assessment tests.

Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia.

Ischemia-induced neuronal damage has been linked to elevated production of reactive oxygen species (ROS) both in animal models and in humans. NADPH oxidase enzymes (NOX-es) are a major enzymatic source of ROS, but their role in brain ischemia has not yet been investigated. The present study was carried out to examine the expression of NOX4, one of the new NADPH oxidase isoforms in a mouse model of focal permanent brain ischemia. We demonstrate that NOX4 is expressed in neurons using in situ hybridization and immunohistochemistry. Ischemia, induced by middle cerebral artery occlusion resulted in a dramatic increase in cortical NOX4 expression. Elevated NOX4 mRNA levels were detectable as early as 24 h after the onset of ischemia and persisted throughout the 30 days of follow-up period, reaching a maximum between days 7 and 15. The early onset suggests neuronal reaction, while the peak period corresponds to the time of neoangiogenesis occurring mainly in the peri-infarct region. The occurrence of NOX4 in the new capillaries was confirmed by immunohistochemical staining. In summary, our paper reports the presence of the ROS producing NADPH oxidase NOX4 in neurons and demonstrates an upregulation of its expression under ischemic conditions. Moreover, a role for NOX4 in ischemia/hypoxia-induced angiogenesis is suggested by its prominent expression in newly formed capillaries.

Decreased blood pressure in NOX1-deficient mice

To understand the role of the superoxide‐generating NADPH oxidase NOX1 in the vascular system, we have generated NOX1‐deficient mice. NOX1‐deficient mice had a moderately decreased basal blood pressure. In response to angiotensin II they showed an almost complete loss of the sustained blood pressure response, while the initial increase was conserved. NOX1‐deficient mice showed a marked reduction in aortic media hypertrophy. Angiotensin II‐induced smooth muscle cell proliferation was conserved, but there was a marked decrease in extracellular matrix accumulation. Our results establish a role for NOX1 in blood pressure regulation and vascular angiotensin II response.

Physical activity reduces systemic blood pressure and improves early markers of atherosclerosis in pre-pubertal obese children.

OBJECTIVES The aim of this study was to determine the effects of physical activity on systemic blood pressure (BP) and early markers of atherosclerosis in pre-pubertal obese children. BACKGROUND Hypertension and endothelial dysfunction are premature complications of obesity. METHODS We performed a 3-month randomized controlled trial with a modified crossover design: 44 pre-pubertal obese children (age 8.9 + or - 1.5 years) were randomly assigned (1:1) to an exercise (n = 22) or a control group (n = 22). We recruited 22 lean children (age 8.5 + or - 1.5 years) for baseline comparison. The exercise group trained 60 min 3 times/week during 3 months, whereas control subjects remained relatively inactive. Then, both groups trained twice/week during 3 months. We assessed changes at 3 and 6 months in office and 24-h BP, arterial intima-media thickness (IMT) and stiffness, endothelial function (flow-mediated dilation), body mass index (BMI), body fat, cardiorespiratory fitness (maximal oxygen consumption [VO(2)max]), physical activity, and biological markers. RESULTS Obese children had higher BP, arterial stiffness, body weight, BMI, abdominal fat, insulin resistance indexes, and C-reactive protein levels, and lower flow-mediated dilation, VO(2)max, physical activity, and high-density lipoprotein cholesterol levels than lean subjects. At 3 months, we observed significant changes in 24-h systolic BP (exercise -6.9 + or - 13.5 mm Hg vs. control 3.8 + or - 7.9 mm Hg, -0.8 + or - 1.5 standard deviation score [SDS] vs. 0.4 + or - 0.8 SDS), diastolic BP (-0.5 + or - 1.0 SDS vs. 0 + or - 1.4 SDS), hypertension rate (-12% vs. -1%), office BP, BMI z-score, abdominal fat, and VO(2)max. At 6 months, change differences in arterial stiffness and IMT were significant. CONCLUSIONS A regular physical activity program reduces BP, arterial stiffness, and abdominal fat; increases cardiorespiratory fitness; and delays arterial wall remodeling in pre-pubertal obese children. (Effects of Aerobic Exercise Training on Arterial Function and Insulin Resistance Syndrome in Obese Children: A Randomized Controlled Trial; NCT00801645).

SURVIVAL AND POTENTIAL YEARS OF LIFE LOST AFTER HIP FRACTURE IN MEN AND AGE-MATCHED WOMEN

Abstract: Hip fracture is associated with a higher mortality rate in men than in women. However, mean age of men and women with hip fracture differs markedly. Thus, some of the differences in the clinical pattern and outcome between genders could be related to different ages. To avoid the influence of age on gender-specific outcome, we analyzed prefracture conditions and hip fracture outcome in a cohort of men and of age-matched women. Risk factors for low bone mass were recorded in 106 men (mean age ± SD, 80.3 ± 9.3 years) and 264 age-matched women (mean age 81.4 ± 8.0) with hip fracture. We compared mortality rate, survival, years of potential life lost and modification of housing conditions. These outcomes were prospectively assessed during an average 3.6 years follow-up (up to 7 years). Men with hip fracture differed from age-matched hip-fractured women by a higher alcohol and tobacco consumption, a greater frequency of living in couple, and by less prevalent fractures. Mortality rate after hip fracture was significantly higher in men (RR = 1.74, 95% CI 1.34–2.24). Since mortality is higher in the general male population, we compared reduction in life expectancy taking into account the gender-specific mortality rate. The excess mortality in each age-group of hip-fractured patients, which was measured during the whole follow-up period, and is an estimate of death attributable to fracture, did not differ between genders. Reduction in life expectancy due to hip fracture was similar in both genders (5.9 ± 4.5 and 5.8 ± 4.8 years, in men and women, respectively; NS), but the proportion of the years of life lost was higher in men (70 ± 33%) than in women (59 ± 42%, p < 0.01). It was concluded that for the same age, mortality rate after hip fracture was higher in men than in women. Although the reduction in life expectancy was similar in both genders, the proportion of the years of life lost was higher in men, suggesting a worse impact of hip fracture on survival in men, even after consideration of the higher mortality rate in the general male population.

Cortical Microinfarcts and Demyelination Significantly Affect Cognition in Brain Aging

Background and Purpose— Microvascular lesions are common in brain aging, but their clinical impact is debated. Methodological problems such as the masking effect of concomitant pathologies may explain discrepancies among previous studies. To evaluate the cognitive consequences of such lesions, we prospectively investigated elderly individuals with various degrees of cognitive impairment but without significant neurofibrillary tangle pathology or macrovascular lesions. Methods— This was a clinicopathological study of 45 elderly individuals. Cognitive status was assessed prospectively with the Clinical Dementia Rating (CDR) scale; neuropathological evaluation included A&bgr;-protein deposition staging and bilateral semiquantitative assessment of cortical microinfarcts, focal cortical and white matter glioses, and diffuse white matter and periventricular demyelination. Results— In a univariate logistic regression model, cortical microinfarcts explained 36.1% of the variability in CDR; periventricular demyelination, 10.6%; and diffuse white matter demyelination, 4.6%. After controlling for age and A&bgr;-protein deposition, cortical microinfarcts were the best predictor of cognitive status (19.9% of CDR variability), whereas periventricular and diffuse white matter demyelination accounted for 9.7% and 5.4% of CDR variability, respectively. Altogether, these 3 types of microvascular lesions explained 27.9% of the clinical variability. Focal cortical and white matter glioses were not related to clinical outcome. Conclusions— Our data imply that cortical microinfarcts and both periventricular and deep white matter demyelination contribute significantly to the progression of cognitive deficits in brain aging. In contrast, the neuropathological evaluation of focal cortical and white matter gliosis has no clinical validity.

Risk factors for Visual loss in giant cell (temporal) arteritis : A prospective study of 174 patients

OBJECTIVE To determine the risk factors--especially the effects of thrombocytosis--for permanent visual loss in patients with temporal arteritis. METHODS One hundred seventy-four patients with temporal arteritis (147 biopsy proven) were prospectively observed for the development of permanent visual loss. We used multivariate logistic regression analysis to determine which of 17 pretreatment characteristics were associated with visual loss. RESULTS Visual ischemic manifestations occurred in 48 (28%) patients, including permanent visual loss in 23 (13%) patients. The independent predictors associated with an increased risk of permanent visual loss were a history of transient visual ischemic symptoms (odds ratio [OR] = 6.3; 95% confidence interval [CI]: 1.4 to 29; P = 0.02) and a higher platelet count (OR = 3.7 per SD; 95% CI: 1.8 to 7.9; P = 0.001). The presence of constitutional symptoms (OR = 0.14; 95% CI: 0.02 to 0.77, P = 0.01), polymyalgia rheumatica (OR = 0.04; 95% CI: 0.01 to 0.48, P = 0.02), and C-reactive protein level (OR = 0.35 per SD; 95% CI: 0.13 to 0.92, P = 0.03) were associated with a reduced risk. Upper limb artery involvement was excluded from the multivariate model, as no patients with that problem developed permanent visual loss. Of the 87 patients who presented with thrombocytosis (platelet count >400 x 10(9)/L), 32 (37%) developed ischemic visual symptoms, compared with 16 (18%) of those without thrombocytosis. CONCLUSIONS An elevated platelet count is a risk factor for permanent visual loss in temporal arteritis. The finding of thrombocytosis in a patient with suspected temporal arteritis should emphasize the need for urgent treatment, with consideration of using inhibitors of platelet aggregation or anticoagulation therapy.

Expression of NOX1, a superoxide-generating NADPH oxidase, in colon cancer and inflammatory bowel disease

Reactive oxygen species (ROS) are at the centre of many physiological and pathological processes. NOX1, a ROS‐producing NADPH oxidase, is highly expressed in the colon but its function in colonic physiology or pathology is still poorly understood. It has been suggested to play a role in host defence, but also in cell growth and possibly malignant transformation. In this study we characterized NOX1 expression in human colon samples derived from healthy control subjects and patients with colon cancer or inflammatory bowel disease (IBD). NOX1 mRNA expression was assessed by dot‐blot hybridization, real‐time PCR and in situ hybridization, using samples derived from surgical specimens from patients undergoing colon resection. In normal tissues, NOX1 expression was low in the ileum, intermediate in the right colon, and high in the left colon (p = 0.0056 right vs. left colon). NOX1 mRNA levels were not influenced by factors linked to colon tumourigenesis, such as age or sex. Moreover, there was no statistical difference in NOX1 expression between samples derived from adenomas, well differentiated or poorly differentiated colon adenocarcinomas. At a cellular level, NOX1 was highly expressed in colon epithelial cells, both within the crypts and on the luminal surface. In addition, a population of lymphocytes, particularly in the appendix, showed NOX1 expression. Lymphocytes in lesions of Crohns disease and ulcerative colitis were also strongly positive for NOX1. In conclusion, NOX1 is an enzyme that is constitutively expressed in colon epithelium and is not associated with tumourigenesis. Its distribution in crypts and on the luminal surface, as well as its left‐to‐right gradient in the colon, suggests a role in host defence function. In addition to the known epithelial localization, we define lymphocytes as a novel site of NOX1 expression, where it may potentially be involved in the pathogenesis of inflammatory bowel diseases. Copyright