Neuroinflammation and ß amyloid deposition in Alzheimer's disease: in vivo quantification with molecular imaging.

BACKGROUND/AIMS: Neuroinflammation plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Its relationship with underlying ß amyloid deposition remains unclear. In vivo visualization of microglial activation has become possible with the development of molecular imaging ligands when used with positron emission tomography (PET). The translocator protein (TSPO) is upregulated during neuroinflammation. Consequently, targeting TSPO with radiolabeled ligands for PET is an attractive biomarker for neuroinflammation. METHODS: A review of the research literature on PET imaging which studied in vivo neuroinflammation in AD subjects and its relationship with amyloid load was performed, including papers published between 2001 and 2012. RESULTS: Six studies were included using either [(11)C]PK-11195 or another non-TSPO radioligand that binds to the monoaminooxidase B. All the studies evaluated amyloid load with [(11)C]PIB. Microglial activation and astrocytosis are potentially early phenomena in AD. However, the individual levels of amyloid deposition and microglial activation were not correlated. CONCLUSION: Noninvasive in vivo molecular imaging to visualize neuroinflammation in AD may contribute to our understanding of the kinetics of neuroinflammation and its relationship to the hallmarks of the disease. Both are important for the development of future therapeutic modalities and for quantifying the efficacy of future disease-modifying treatments.

Prevention of the ß-amyloid peptide-induced inflammatory process by inhibition of double-stranded RNA-dependent protein kinase in primary murine mixed co-cultures.

BACKGROUND: Inflammation may be involved in the pathogenesis of Alzheimer's disease (AD). There has been little success with anti-inflammatory drugs in AD, while the promise of anti-inflammatory treatment is more evident in experimental models. A new anti-inflammatory strategy requires a better understanding of molecular mechanisms. Among the plethora of signaling pathways activated by ß-amyloid (Aß) peptides, the nuclear factor-kappa B (NF-κB) pathway could be an interesting target. In virus-infected cells, double-stranded RNA-dependent protein kinase (PKR) controls the NF-κB signaling pathway. It is well-known that PKR is activated in AD. This led us to study the effect of a specific inhibitor of PKR on the Aß42-induced inflammatory response in primary mixed murine co-cultures, allowing interactions between neurons, astrocytes and microglia. METHODS: Primary mixed murine co-cultures were prepared in three steps: a primary culture of astrocytes and microglia for 14 days, then a primary culture of neurons and astrocytes which were cultured with microglia purified from the first culture. Before exposure to Aß neurotoxicity (72 h), co-cultures were treated with compound C16, a specific inhibitor of PKR. Levels of tumor necrosis factor-α (TNFα), interleukin (IL)-1ß, and IL-6 were assessed by ELISA. Levels of PT451-PKR and activation of IκB, NF-κB and caspase-3 were assessed by western blotting. Apoptosis was also followed using annexin V-FITC immunostaining kit. Subcellular distribution of PT451-PKR was assessed by confocal immunofluorescence and morphological structure of cells by scanning electron microscopy. Data were analysed using one-way ANOVA followed by a Newman-Keuls' post hoc test RESULTS: In these co-cultures, PKR inhibition prevented Aß42-induced activation of IκB and NF-κB, strongly decreased production and release of tumor necrosis factor (TNFα) and interleukin (IL)-1ß, and limited apoptosis. CONCLUSION: In spite of the complexity of the innate immune response, PKR inhibition could be an interesting anti-inflammatory strategy in AD.

NFL strongly correlates with TNF-R1 in the plasma of AD patients, but not with cognitive decline.

Peripheral inflammation mechanisms involved in Alzheimer's disease (AD) have yet to be accurately characterized and the identification of blood biomarker profiles could help predict cognitive decline and optimize patient care. Blood biomarkers described to date have failed to provide a consensus signature, which is mainly due to the heterogeneity of the methods used or the cohort. The present work aims to describe the potential informativity of peripheral inflammation in AD, focusing in particular on the potential association between the level of plasma neurofilament light (NFL), peripheral inflammation (by quantifying IL-1ß, IL-6, TNFα, CCL5, TNF-R1, sIL-6R, TIMP-1, IL-8 in blood) and cognitive decline (assessed by the MMSE and ADAScog scales) through a 2-year follow-up of 40 AD patients from the Cytocogma cohort (CHU Poitiers, Pr M. Paccalin). Our results show for the first time a strong correlation between plasma NFL and TNF-R1 at each time of follow-up (baseline, 12 and 24 months), thus opening an interesting perspective for the prognosis of AD patients.

Determinants of doctors' antibiotic prescriptions for patients over 75 years old in the terminal stage of palliative care.

INTRODUCTION: Notwithstanding high prevalence of presumably bacterial infections in elderly persons (EP) in palliative care (PC), there exists no recommendation on the role of antibiotic therapy (ABP) in this type of situation. OBJECTIVE: To describe the determinants of antibiotic prescription by general practitioners (GP) and by doctors practicing in institutions (DPI) for patients>75 years, in end-of-life situations in PC. METHOD: Descriptive investigation by anonymous self-administered questionnaire disseminated in France by e-mail. RESULTS: A total of 301 questionnaires analyzed: 113 GP, 188 DPIs. The latter were mainly geriatricians (69, 36.6%) and infectologists/internists (41, 21.8%). Sixty-three (55,75%) GPs and 144 (78.7%) DPIs stated that they had prescribed antibiotics. Practice in "EHPAD" retirement homes or intensive care was often associated with non-prescription of antibiotics. Age, PC training and number of patients monitored bore no influence. Family involvement in decision-making was more frequent for GPs than for DPIs. The main purpose of antibiotic therapy was to relieve different symptoms (fever, respiratory congestion, functional urinary signs). Most of the doctors (81%) had previously encountered complications (allergy, adverse effect), which represented the main causes of treatment discontinuation. CONCLUSION: Antibiotic use in end-of-life EPs in PC seems frequent. In accordance with the principle of beneficence, its goal of often symptom-related; that said, in the absence of scientific data, antibiotic prescription in end-of-life situations should be individualized in view of observing the other ethical caregiving principles (beneficence, non-maleficence, justice, patient autonomy) and re-evaluated daily.

Images in gerontology: a case report.

Left ventricular aneurysm can complicate acute myocardial infarction. Clinical and electrocardiogram features are not specific. We describe a case with asymptomatic left ventricular aneurysm diagnosed by computerized-tomography angiography.

[Vaccine coverage against influenza and pneumococcal infections in patients aged 65 and over: a survey on 299 outpatients]. / Couverture vaccinale antigrippale et antipneumococcique à partir de 65ans : étude sur 299 patients ambulatoires.

INTRODUCTION: There is no compulsory vaccination in the adult population. Therefore, vaccine coverage appears heterogeneous. METHODS: We performed a 2-month survey to evaluate the vaccine coverage administered by 11 general practitioners in their patients aged 65 and over, with a focus on influenza vaccination recommended in France for individuals being 65 years old or more and on pneumococcal vaccination indicated but not recommended in the same age population; analysing the reasons for non vaccine administration against influenza and pneumococcal infections. RESULTS: Two hundred and ninety-nine patients were interviewed, mean age of 77+/-6,9 years; 76,3% were vaccinated against influenza; only nine patients out of the 46 having a recommendation for pneumococcal vaccine were immunized (19,6%). The main reasons for non vaccination were the fear of vaccine for influenza and a lack of information for the pneumococcal vaccine. CONCLUSION: These results underline the low prevalence for pneumococcal vaccine in ambulatory patients, despite recommendations. Previous studies with controversial data might explain the low prevalence. Better information of the expected benefit of this vaccine and better correlation between indications and recommendations could increase its coverage.

Treatment compliance with European guidelines and prognosis of Clostridium difficile infection according to age.

OBJECTIVE: Age>65 years is associated with the recurrence and poor prognosis of Clostridium difficile infection (CDI). Data on elderly patients (≥75 years) is scarce, and little is known about compliance with European guidelines in terms of specific treatment. We aimed to analyze the treatment and prognosis of CDI in two groups of patients aged

Comprehensive geriatric assessment in older patients suffering from infective endocarditis. A prospective multicentric cohort study.

OBJECTIVES: The aim was to describe the impact of infective endocarditis (IE) on functional, cognitive and nutritional statuses, and to estimate the influence of these parameters on surgical management and mortality. METHOD: This was a prospective study over 13 months in 14 French hospitals, including patients ≥75 years of age with definite or possible IE. A comprehensive geriatric assessment (CGA) was performed during the first week of hospitalization, including a retrospective estimation of functional status 2 months before hospitalization, and 3 months after. RESULTS: A total of 120 patients were included (mean age 83.1 ± 5.0 (75-101) years). IE was associated with a dramatic impairment of functional status between 2 months prior hospitalization and the first geriatric evaluation (90.8% able to walk vs. 35.5% (p < 0.0001), ADL (Activities in Daily Living) 5.0 ± 1.7 vs. 3.1 ± 2.1 (p < 0.0001)). The 19 operated patients (15.8%) had less comorbidities (cumulative illness rating scale geriatric 10.8 ± 8.2 vs. 15.3 ± 7.1 (p 0.0176)), better functional (ADL 5.9 ± 0.4 vs. 4.9 ± 1.8 (p 0.0171) and nutritional (mini nutritional assessment 20.4 ± 5.0 vs. 17.3 ± 6.2 (p 0.0501)) statuses than non-operated patients. Among all infectious, cardiac and geriatric parameters, body mass index (HR 0.9, range 0.8-1, p 0.05) and ADL at the time of the first evaluation (HR 0.7, range 0.6-0.9, p 0.002) were the sole independent predictors of the 3-month (32.5%) and 1-year mortality (42.5%). Three months later, the 57 assessed patients only partially recovered their ADL (3.7 ± 1.9 vs. 5.3 ± 1.4 2 months prior hospitalization and 4.6 ± 1.9 at the first CGA; p < 0.0001). CONCLUSION: Functional and nutritional abilities are crucial components that can be accurately explored through a CGA when managing IE in oldest patients.

[Late diagnosis of Dandy-Walker syndrome revealed by gait disorders in an elderly]. / Diagnostic tardif d'un syndrome de Dandy-Walker révélé par des troubles de la marche chez le sujet âgé.

The Dandy-Walker syndrome is a rare malformation usually diagnosed during pregnancy or early in the course of life. We report a case in an elderly hospitalised for gait disorders and recurrent falls. Cerebral MRI revealed hydrocephalus and posterior fossa cyst. The patient improved after ventriculocisternostomia.

[Diagnosis and epidemiological surveillance of influenza and respiratory syncytial virus infections: interest of multiplex PCR]. / Diagnostic et surveillance épidémiologique des infections grippales et à virus respiratoire syncytial: intérêt de la PCR multiplex.

OBJECTIVE: Respiratory infections require a rapid etiological diagnosis for efficient management of cases. We evaluated multiplex PCR used for the diagnosis and the epidemiological surveillance of influenza and respiratory syncytial virus (RSV) infections. PATIENTS AND METHODS: Our study included 278 patients (mean age: 37.2+/-22.9 years) with flu or flu-like syndromes, consulting physicians affiliated with the GROG Poitou-Charentes or hospitalized in the Poitiers teaching hospital. A multiplex PCR detecting A(H3), A(H1) and B influenza viruses, and RSV A and B, was performed with both a direct examination by immunofluorescence and cell-culture. RESULTS: We diagnosed a viral infection in 139 (50.0%) patients: 99 cases of influenza A(H3), 2 cases of influenza A(H1), 28 cases of influenza B and 11 cases of RSV infections. The diagnosis yield in GROG patients (52.3%) was significantly higher than that observed in hospitalized patients (34.5%) (P=0.04). All techniques were correlated in 61% of cases. The multiplex PCR yielded 22.3% more positive samples compared to the conventional techniques. All positive samples by conventional techniques were also positive by multiplex PCR. We observed a perfect correlation between viral types and subtypes determined by PCR and cell-culture. CONCLUSION: Multiplex PCR is a sensitive technique allowing an efficient and rapid diagnosis of respiratory infections due to influenza and RSV.

[Identification errors and delusions of false identification in Alzheimer's disease: a regional survey]. / Troubles de l'identification et délires d'identité dans la maladie d'Alzheimer: une enquête régionale.

INTRODUCTION: Misidentification syndromes are the main symptoms in Alzheimer's disease. Underlain by complex cognitive, agnosic, and amnesic disturbances of degenerative etiology, they can be expressed by misidentification delusions, as in psychoses. To date, research has focused on identification disturbances of persons selected according to various definitions. OBJECTIVE: Our main objective was to evaluate the frequency of identification disturbances among patients suffering from Alzheimer's disease within the current conditions of diagnosis and treatment. The secondary objective aimed to establish a detailed analysis of symptoms and clinical correlations, and evaluate the effects of the troubles on the caregiver. METHODS: We conducted a regional survey using a questionnaire designed for the caregiver, proposed to the 60 geriatric doctors and neurologists in the Poitou-Charentes region of France, for all patients suffering from Alzheimer's disease (defined according to DSM IV criteria) seen between June 1st and August 31st of 2003. Statview software was used for statistical analysis. RESULTS: The survey was completed for 104 patients: 69.5 percent women and 30.5 percent men, with a mean age of 79 years. The majority of the patients were seen by a neurologist and presented an average cognitive deficiency (MMS ranging from 11 to 20). An identification disturbance, whether or not it was delusional, all domains included, was found in 81.6 percent of the patients and was related to a more severe cognitive deficiency and greater hardship on the part of the caregiver. DISCUSSION: We observed a high prevalence of identification disturbance, which can be explained by the systematic and exhaustive search for identification disturbance. The most frequent disturbance concerned the identification of places, whereas self-identification was less often affected; the authentic Capgras delusion was found less often. CONCLUSION: The study of identification disturbances in Alzheimer's disease can contribute to a better understanding of the cognitive, psychopathological, and physiopathological aspects of the disease as well as to a better knowledge and better care for the patient.

[Primary localized amyloidosis of the urinary tract. A case series of five patients]. / Amylose primitive localisée à l'appareil urinaire. A propos de cinq cas.

PURPOSE: To describe the clinical and radiographic features of patients with primary localized amyloidosis of the urinary tract. METHODS: We report a case of localized amyloidosis of the ureters and bladder. The medical records of four other cases from the French Register of localized amyloidosis were reviewed. RESULTS: The mean age of three men and two women was 53 years. All patients presented with gross hematuria, four patients presented with renal colic, only one patient had irritative lower urinary tract symptoms. Ureter and bladder were involved in three patients, both ureters in two patients and the bladder only, in one patient. Clinical and radiographic presentations mimicked a neoplasia excluded by histologic analysis. Immunohistochemical study was performed in only two cases and revealed lambda light chain amyloidosis. The median follow-up was eight years. Various treatments were performed, and recurrences occurred in two cases. None of the five patients developed monoclonal gammapathy or systemic amyloidosis. CONCLUSION: Primary localized amyloidosis of the urinary tract is a rare disorder and can easily be confused with a neoplasm. The physiopathology is unknown, the prognosis is usually good. There is no specific treatment, and repeated work-up for systemic amyloidosis is unnecessary as local recurrences appear to be the main complication.

Subcutaneously administered antibiotics: a national survey of current practice from the French Infectious Diseases (SPILF) and Geriatric Medicine (SFGG) society networks.

A national survey was performed to explore antibiotic prescription by the subcutaneous (sc) route among French infectious diseases and geriatric practitioners. Among the participating physicians, 367 (96.1%) declared administering sc antibiotics at some point. Ceftriaxone was prescribed sc by all but one, and ertapenem, teicoplanin, aminoglycosides and amoxicillin by 33.2%, 39.2%, 35.1% and 15.3%, respectively. The sc route was resorted to mainly in case of unavailable oral, intravenous or intramuscular routes, especially during palliative care. Pain, skin necrosis and lack of efficacy were the main adverse effects, reported by 70.8%, 12.8% and 19.9% of practitioners, respectively. Further studies are needed to precise the indications, modalities and tolerance of sc antibiotic use.

[Effect of age on the prognosis of infectious endocarditis]. / Influence de l'âge sur le pronostic de l'endocardite infectieuse.

The aim of this study was to evaluate the influence of age on the prognosis of infectious endocarditis. A retrospective study from 1987 to 1997 of 136 patients with infectious endocarditis on native, prosthetic valves or cardiac pacing catheter was performed. The outcome was analysed with the help of general practitioners. Two groups of patients were compared: 87 patients of 65 years of age or more (Group 1) and 49 patients under 65 years of age (Group 2). With a follow-up period of 5 years, the global mortality was 35%, but greater in Group 1 (p = 0.06). Cardiac failure was the main cause of death. The mortality was significantly higher in patients who were not operated (p < 0.002). The authors conclude that age of over 65 does not significantly worsen the prognosis of infectious endocarditis. The absence of surgery seems to be an indirect factor of a poor prognosis. Long-term follow-up of patients is necessary to diagnose and treat cardiac failure at an early stage and to consider referral for surgery.

[Treatment of high-grade, disseminated non-Hodgkin's lymphoma in elderly patients]. / Traitement du lymphome malin non hodgkinien de haut grade et de stade disséminé du sujet âgé.

PURPOSE: Treatment of non-Hodgkin's lymphoma (NHL) in the elderly is difficult because of an increased risk of toxicity and frequent chronic or debilitating diseases. The aim of this paper is to describe the main studies in this field. CURRENT KNOWLEDGE AND KEY POINTS: Most recent clinical trials deal with anthracyclin or assimilated drugs regimens. Potential interest of chemotherapy and associated immunotherapy is on study. Without any influence on survival duration, haematopoietic growth factors seem to improve the tolerance of the treatment. FUTURE PROSPECTS AND PROJECTS: For elderly patients with good performance status and without severe co morbidity, curative strategy with anthracyclin-containing regimen like CHOP is still the standard chemotherapy. Association with rituximab improves the prognosis. For patients with poor performance status and/or associated disease, optimal strategy remains to be defined with quality of life evaluation.

[Severe pulmonary manifestation in adult-onset Still's disease]. / Manifestation pulmonaire grave de la maladie de Still de l'adulte.

Adult onset Still's disease may sometimes be complicated by severe manifestations. We report here a case of adult Still's disease with acute respiratory failure requiring mechanical ventilation.

[Details of meningitis in the elderly]. / Particularités des méningites du sujet âgé.

PURPOSE: Elderly patients being more at risk for infections than younger people, this study was aimed at defining the epidemiological and clinical features of meningitis in this population, with the objective of improving diagnosis and management. METHODS: Over a period of 10 years, all cases admitted to an infectious diseases unit for acute meningitis were reviewed. Patients infected by human immunodeficiency virus (HIV), fungi meningitis, and who were younger than 15 years of age were excluded from the study. According to age, two groups were constituted (group A: < 65 years and group B: > or = 65 years) and compared. RESULTS: One hundred fifty-two patients were included in the study: 110 (72.4%) in group A (29 with bacterial and 81 with viral meningitis) and 42 (26.7%) in group B (32 with bacterial and ten with viral meningitis); the mean age was, respectively, 32.7 +/- 12.9 years (range: 15-61 years) and 75.9 +/- 7.6 years (range: 65-94 years). Diagnosis was less frequently evoked in the elderly (n = 11; 26%) than in younger patients (n = 78; 71%) (P < 0.001). Streptococcus pneumoniae, Listeria monocytogenes, and herpes simplex virus were the three most common causal agents in group B. Confusion was the most common symptom among the elderly (88 vs. 17%; P < 0.001). The mortality rate was more important in group B than in group A (11.9 vs. 2.7%; P = 0.04). CONCLUSIONS: Diagnosis of acute meningitis is difficult and must be evoked in the presence of any new neurologic sign. Cranial computerized tomography should not delay lumbar puncture, except in the presence of focal neurologic symptoms. Antimicrobial therapy takes into account the bacterial epidemiology.

[RS3PE: a clinical diagnosis, a prognosis more simple than its name]. / RS3PE: un diagnostic clinique, une évolution plus simple que le nom.

INTRODUCTION: RS3PE syndrome (remittive symmetrical seronegative synovitis with pitting edema) was first described by MacCarthy in 1985. It is a rare type of seronegative polyarthritis occurring in the elderly. METHODS: Retrospective report of 13 cases (including eight male and five female patients; mean age 76.7 +/- 3.7 years) and search for previously reported cases, using the Medline database. RESULTS: Pitting edema was present at onset of disease in nine cases. Joint arthritis was bilateral, occurring in the wrist (13 cases), shoulder (six cases), elbow (six cases), knee (six cases), ankle (four cases), metacarpophalangeal (four cases) and hip (one case). Radiographies were normal. Mean erythrocyte sedimentation rate was 62 +/- 19 mm at the first hour and mean C-reactive protein level was 73 +/- 35 mg/L. Mild cholestasis was present in four of the seven patients for whom data were available. HLA B7 was present in five out of 12 cases (42%). Improvement was favorable, occurring over 7 months. Mean follow-up was 22.2 months. Fifty-nine other cases have been described in the literature. This syndrome, which affects the elderly, appears to be rare. Its clinical presentation is quite constant, with sudden onset, symmetrical polyarthritis and pitting edema. Its evolution, often long, is favorable. Rheumatoid arthritis and polymyalgia rheumatica are the main differential diagnoses. CONCLUSION: Due to its favorable outcome and the usefulness of a mild corticotherapy, this syndrome, though rare, should be diagnosed where necessary in elderly patients.

[Premature cerebral vascular accidents after initiation of steroid therapy in Horton disease]. / Accidents vasculaires encéphaliques précoces après instauration d'une corticothérapie au cours de la maladie de Horton.

INTRODUCTION: Steroid therapy remains the standard treatment for giant cell arteritis but is sometimes incriminated in the occurrence of ischemic events, particularly in the early phase of the disease. EXEGESIS: We report four cases of ischemic events observed early after initiation of steroid therapy in giant cell arteritis. We also reviewed the literature. CONCLUSION: Though the close temporal relationship between the initiation of steroids and the occurrence of ischemic events suggests a causative link, other factors such as arteritis itself or arteriosclerosis would also play a role. Systematic prescription of an anticoagulant should be discussed at the initial phase of treatment of giant cell arteritis.

[Primary thyroid lymphoma: report of 8 cases]. / Lymphome malin primitif de la thyroïde: à propos de huit cas.

PURPOSE: Primary thyroid lymphoma (PTL) is a rare disease. Few patients are reported in the literature. We report eight new cases of PTL with long-term follow-up. RESULTS: The clinical presentation was usually an enlarging neck mass squeezing surrounding structures. The diagnosis was established after thyroidectomy with histopathologic and immunohistochemical studies. Histology showed infiltrates of chronic lymphocytic thyroiditis in all cases. Three patients had thyroid lymphoma arising from mucosa-associated lymphoid tissue. One patient died postoperatively. The other seven were treated with combined chemotherapy and radiotherapy. They were still in remission after a 6-year follow-up. CONCLUSION: Diagnosis of PTL should be suspected when there is a recent thyroid enlargement. Surgery associated with chemotherapy and radiation gave good results in our study with long-term follow-up, though surgery was not always recommended in previous reports.