Steroid responsive encephalopathy in cerebral amyloid angiopathy: a case report and review of evidence for immunosuppressive treatment

Cerebral amyloid angiopathy (CAA) is a common but often asymptomatic disease, characterized by deposition of amyloid in cerebral blood vessels. We describe the successful treatment of CAA encephalopathy with dexamethasone in a patient with CAA-related inflammation causing subacute progressive encephalopathy and seizures, which is an increasingly recognized subtype of CAA. The two pathological subtypes of CAA-related inflammation are described and a review of the literature is performed concerning immunosuppressive treatment of CAA-related inflammation with special attention to its pathological subtypes. Immunosuppressive therapy appears to be an appropriate treatment for CAA encephalopathy

Neuroinflammation in Alzheimer's disease wanes with age

<p>Abstract</p> <p>Background</p> <p>Inflammation is a prominent feature in Alzheimer's disease (AD). It has been proposed that aging has an effect on the function of inflammation in the brain, thereby contributing to the development of age-related diseases like AD. However, the age-dependent relationship between inflammation and clinical phenotype of AD has never been investigated.</p> <p>Methods</p> <p>In this study we have analysed features of the neuroinflammatory response in clinically and pathologically confirmed AD and control cases in relation to age (range 52-97 years). The mid-temporal cortex of 19 controls and 19 AD cases was assessed for the occurrence of microglia and astrocytes by immunohistochemistry using antibodies directed against CD68 (KP1), HLA class II (CR3/43) and glial fibrillary acidic protein (GFAP).</p> <p>Results</p> <p>By measuring the area density of immunoreactivity we found significantly more microglia and astrocytes in AD cases younger than 80 years compared to older AD patients. In addition, the presence of KP1, CR3/43 and GFAP decreases significantly with increasing age in AD.</p> <p>Conclusion</p> <p>Our data suggest that the association between neuroinflammation and AD is stronger in relatively young patients than in the oldest patients. This age-dependent relationship between inflammation and clinical phenotype of AD has implications for the interpretation of biomarkers and treatment of the disease.</p

Maximal COX-2 and ppRb expression in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia in Alzheimer's disease

Neuronal expression of cyclooxygenase-2 (COX-2) and cell cycle proteins is suggested to contribute to neurodegeneration during Alzheimer's disease (AD). The stimulus that induces COX-2 and cell cycle protein expression in AD is still elusive. Activated glia cells are shown to secrete substances that can induce expression of COX-2 and cell cycle proteins in vitro. Using post mortem brain tissue we have investigated whether activation of microglia and astrocytes in AD brain can be correlated with the expression of COX-2 and phosphorylated retinoblastoma protein (ppRb). The highest levels of neuronal COX-2 and ppRb immunoreactivity are observed in the first stages of AD pathology (Braak 0–II, Braak A). No significant difference in COX-2 or ppRb neuronal immunoreactivity is observed between Braak stage 0 and later Braak stages for neurofibrillary changes or amyloid plaques. The mean number of COX-2 or ppRb immunoreactive neurons is significantly decreased in Braak stage C compared to Braak stage A for amyloid deposits. Immunoreactivity for glial markers KP1, CR3/43 and GFAP appears in the later Braak stages and is significantly increased in Braak stage V-VI compared to Braak stage 0 for neurofibrillary changes. In addition, a significant negative correlation is observed between the presence of KP1, CR3/43 and GFAP immunoreactivity and the presence of neuronal immunoreactivity for COX-2 and ppRb. These data show that maximal COX-2 and ppRb immunoreactivity in neurons occurs during early Braak stages prior to the maximal activation of astrocytes and microglia. In contrast to in vitro studies, post mortem data do not support a causal relation between the activation of microglia and astrocytes and the expression of neuronal COX-2 and ppRb in the pathological cascade of AD

Preoperative cerebrospinal fluid cytokine levels and the risk of postoperative delirium in elderly hip fracture patients

Aging and neurodegenerative disease predispose to delirium and are both associated with increased activity of the innate immune system resulting in an imbalance between pro- and anti-inflammatory mediators in the brain. We examined whether hip fracture patients who develop postoperative delirium have altered levels of inflammatory mediators in cerebrospinal fluid (CSF) prior to surgery. Patients were 75 years and older and admitted for surgical repair of an acute hip fracture. CSF samples were collected preoperatively. In an exploratory study, we measured 42 cytokines and chemokines by multiplex analysis. We compared CSF levels between patients with and without postoperative delirium and examined the association between CSF cytokine levels and delirium severity. Delirium was diagnosed with the Confusion Assessment Method; severity of delirium was measured with the Delirium Rating Scale Revised-98. Mann-Whitney U tests or Student t-tests were used for between-group comparisons and the Spearman correlation coefficient was used for correlation analyses. Sixty-one patients were included, of whom 23 patients (37.7%) developed postsurgical delirium. Concentrations of Fms-like tyrosine kinase-3 (P=0.021), Interleukin-1 receptor antagonist (P=0.032) and Interleukin-6 (P=0.005) were significantly lower in patients who developed delirium postoperatively. Our findings fit the hypothesis that delirium after surgery results from a dysfunctional neuroinflammatory response: stressing the role of reduced levels of anti-inflammatory mediators in this process. The Effect of Taurine on Morbidity and Mortality in the Elderly Hip Fracture Patient.Registration number: NCT00497978. Local ethical protocol number: NL16222.094.0

The Role of Insulin-Like Growth Factor 1 in Delirium: A Systematic Review and Meta-Analysis

Background: The relationship between delirium and low levels of insulin-like growth factor 1 (IGF-1) is contradictory and uncertain. We hypothesised that low levels of IGF-1 are a predisposing factor for delirium in medical and abdominal surgical cohorts, in contrast to other surgical cohorts. Aims: Systematic review and meta-analysis investigating the association between peripheral levels of IGF-1 and delirium in medical and surgical patients to explore if there are distinct patterns of associations by using subgroup meta-analysis. Methods: PubMed, Scopus, CINAHL, Cochrane, and Embase databases were searched. Inclusion criteria were prospective studies in medical and surgical populations and available data. The following were collected: the setting (surgical/medical), the type (orthopaedic surgery, abdominal, cardiovascular, or medical), the number of participants, mean age, the number of delirious patients, scale/criteria for delirium, IGF-1 levels, and MMSE. Results: Thirteen studies were included and analysed. Low levels of IGF-1 are significantly associated with delirium in abdominal surgical samples and medical samples but not in the other surgical samples. Age, cognition, and the setting (medical vs. surgical) do not have any significant effect on the differences in IGF-1 levels between those with and without delirium. Discussion: Delirium in acute medical and abdominal surgery is triggered by low IGF-1 which may reflect chronic conditions like frailty/cachexia/sarcopenia, while in other surgeries perhaps from an inflammatory process. Conclusions: Low peripheral levels of IGF-1 are a predisposing factor for delirium only in acute medical and abdominal surgery. More studies are needed to confirm and to explore further this finding

Minocycline does not affect amyloid beta phagocytosis by human microglial cells

Activated microglia accumulate in amyloid beta (Abeta) plaques containing amyloid associated factors SAP and C1q in Alzheimer's disease (AD) brain. Microglia are involved in AD pathogenesis by promoting Abeta plaque formation and production of pro-inflammatory cytokines. On the other hand, phagocytosis of Abeta by activated microglia may prevent Abeta-mediated neurotoxicity and Abeta plaque formation. Minocycline, a tetracycline derivative, is neuroprotective in various neurodegenerative models as well as human chronic neurological disorders. Minocycline attenuates the release of TNF-alpha by human microglia upon exposure to a mixture of Abeta, SAP and C1q. Here, we demonstrate that minocycline down-regulates the production of pro-inflammatory cytokines by human microglia without affecting their beneficial activity, phagocytosis of amyloid beta fibril

Head trauma and Alzheimer's disease: A case report and review of the literature

The authors describe a case of a 55 year old woman who was diagnosed with Alzheimer's disease 1.5 years after a car accident in which she experienced a mild concussion. Extensive history taking disclosed no cognitive changes prior to the car accident. The case is discussed in view of the inflammation hypothesis regarding Alzheimer's disease and the role of the apolipoprotein E4 genotype of the patient

Consistent patterns in the inconsistent associations of Insulin-like growth factor 1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin 6 (IL-6) levels with delirium in surgical populations. A systematic review and meta-analysis

Background: Biomarkers for delirium could increase diagnostic accuracy and may help to identify pathological pathways. Until now study findings concerning cytokine levels have been inconsistent. Aims: Systematic review and meta-analysis investigating the association between peripheral levels of Insulin-like Growth Factor-1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin-6 (IL-6) and delirium in surgical patients, and to explore if there are distinct/specific patterns that may potentially explain inconsistent results. Methods: PubMed, Scopus, CINAHL, Cochrane, and EMBASE databases were searched. Inclusion criteria were: prospective studies, surgical populations excluding preoperative delirium, available data. The following were collected: type of operation (orthopaedic, abdominal, etc), the timing of operation (acute, elective, both), demographics, number of participants with delirium, time of preoperative blood withdrawal, and preoperative levels of each biomarker. Results: Low levels of IGF-1 (n = 7 studies) are significantly associated with post-operative delirium in abdominal surgical samples. High levels of C-RP (n = 9) are associated with delirium in acute orthopaedic and elective abdominal operations. IL-6 (n = 14) is a significant predictor of post-operative delirium in a variety of surgical conditions (elective or acute). Discussion: A common pattern exists in the otherwise conflicting reported findings. This similarity may reflect different underling mechanisms and predisposing factors like cachexia and catabolic stages. It seems that delirium in abdominal surgery is triggered by IGF-1 disturbances, while in other surgeries by an inflammatory reaction. Conclusions: Despite the contradictory results concerning the association of IGF-1, C-RP and IL-6 with postoperative delirium, the present meta-analysis shows that there are certain patterns. IL-6 seems a consistent predictor for delirium in surgical samples

Consistent patterns in the inconsistent associations of Insulin-like growth factor 1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin 6 (IL-6) levels with delirium in surgical populations. A systematic review and meta-analysis

Background: Biomarkers for delirium could increase diagnostic accuracy and may help to identify pathological pathways. Until now study findings concerning cytokine levels have been inconsistent. Aims: Systematic review and meta-analysis investigating the association between peripheral levels of Insulin-like Growth Factor-1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin-6 (IL-6) and delirium in surgical patients, and to explore if there are distinct/specific patterns that may potentially explain inconsistent results. Methods: PubMed, Scopus, CINAHL, Cochrane, and EMBASE databases were searched. Inclusion criteria were: prospective studies, surgical populations excluding preoperative delirium, available data. The following were collected: type of operation (orthopaedic, abdominal, etc), the timing of operation (acute, elective, both), demographics, number of participants with delirium, time of preoperative blood withdrawal, and preoperative levels of each biomarker. Results: Low levels of IGF-1 (n = 7 studies) are significantly associated with post-operative delirium in abdominal surgical samples. High levels of C-RP (n = 9) are associated with delirium in acute orthopaedic and elective abdominal operations. IL-6 (n = 14) is a significant predictor of post-operative delirium in a variety of surgical conditions (elective or acute). Discussion: A common pattern exists in the otherwise conflicting reported findings. This similarity may reflect different underling mechanisms and predisposing factors like cachexia and catabolic stages. It seems that delirium in abdominal surgery is triggered by IGF-1 disturbances, while in other surgeries by an inflammatory reaction. Conclusions: Despite the contradictory results concerning the association of IGF-1, C-RP and IL-6 with postoperative delirium, the present meta-analysis shows that there are certain patterns. IL-6 seems a consistent predictor for delirium in surgical samples