Emma Rlc Vardy

Increased Circulating Insulin-like Growth Factor-1 in Late-onset Alzheimer's Disease

BACKGROUNDnInsulin-like growth factor (IGF)-1 has been implicated in the pathogenesis of Alzheimers disease (AD).nnnMETHODSnWe compared the level of circulating total and bioavailable IGF-1, by simultaneous measurements of IGF-1 and IGF binding protein (IGFBP)-3, between 87 patients diagnosed with AD and 126 age and sex matched control subjects without cognitive impairment. Blood samples were collected and IGF-1 and IGFBP-3 measured by ELISA. Subjects were also genotyped for apolipoprotein E.nnnRESULTSnTotal circulating IGF-1 levels were significantly raised in the AD group as compared to the control group (p=0.022). There was no significant difference in the circulating level of IGFBP-3 between the two groups. When the IGF-1 levels were ratioed against IGFBP-3 levels as an indicator of unbound, bioavailable circulating IGF-1, there was a significant increase in the molar IGF-1:IGFBP-3 ratio in the AD subjects (0.181 +/- 0.006) as compared to the controls (0.156 +/- 0.004) (p< 0.001). Logistic regression analysis revealed that an increase in the IGF-1:IGFBP-3 molar ratio increased the risk of AD significantly.nnnCONCLUSIONnThe results of increased total and free circulating IGF-1 support the hypothesis that in its early stages late-onset AD reflects a state of resistance to IGF-1.

Emerging therapeutics for Alzheimer's disease

Alzheimer’s disease (AD) is the most common form of dementia, with prevalence and the accompanying socioeconomic impact set to increase over the coming decades. Currently available medications result, at best, in modest cognitive improvement. With increasing understanding of the underlying pathology, new therapeutic targets are being identified at an ever-increasing rate. The key pathological events in the AD brain are deposition of insoluble amyloid-β peptide (Aβ), formation of neurofibrillary tangles and neuroinflammation leading, ultimately, to neuronal cell death. Each of these will be considered, in detail, in terms of the variety of therapeutic approaches currently being investigated and mechanisms that may prove amenable to intervention in the future.

Plasma Angiotensin-Converting Enzyme in Alzheimer's Disease

The insertion allele in the gene encoding angiotensin-converting enzyme (ACE) is a risk factor for Alzheimers disease (AD) and ACE is one of several peptidases that have the ability to degrade the neurotoxic amyloid-beta peptide. ACE is a membrane-bound peptidase that is also present in a soluble form in plasma as a result of a zinc metalloprotease-mediated shedding event. Here we aimed to determine whether there is a difference in ACE in the plasma of late-onset clinically diagnosed AD patients (n = 94) as compared to age-matched non-demented control subjects (n = 188). Plasma ACE was lower in the AD subjects as compared to the controls both at baseline (p = 0.072) and after two years (p = 0.05). There was a greater reduction in plasma ACE in the AD subjects as compared to the control subjects over the two years. Plasma ACE did not correlate with cognitive function. The observed reduction in plasma ACE in AD may reflect a general decrease in the zinc metalloprotease-mediated shedding of a subset of membrane-bound proteins.

Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia

Impairment of brain-glucose uptake and brain-copper regulation occurs in Alzheimer’s disease (AD). Here we sought to further elucidate the processes that cause neurodegeneration in AD by measuring levels of metabolites and metals in brain regions that undergo different degrees of damage. We employed mass spectrometry (MS) to measure metabolites and metals in seven post-mortem brain regions of nine AD patients and nine controls, and plasma-glucose and plasma-copper levels in an ante-mortem case-control study. Glucose, sorbitol and fructose were markedly elevated in all AD brain regions, whereas copper was correspondingly deficient throughout (all Pu2009<u20090.0001). In the ante-mortem case-control study, by contrast, plasma-glucose and plasma-copper levels did not differ between patients and controls. There were pervasive defects in regulation of glucose and copper in AD brain but no evidence for corresponding systemic abnormalities in plasma. Elevation of brain glucose and deficient brain copper potentially contribute to the pathogenesis of neurodegeneration in AD.

POD14 Amyloid PET using 18F-AV-45 in Alzheimer's disease and frontotemporal dementia: first UK results

Introduction 18F-AV-45 (Florbetapir F-18) is a novel 18F-labelled positron emission tomography (PET) tracer for in vivo imaging of cerebral amyloid deposition. Here we present preliminary results for differentiation between Alzheimers disease (AD) and frontotemporal dementia (FTD) using this novel tracer, which is being applied in the UK for the first time. Methods A study using 18F-AV-45 PET is to be performed in 15 subjects with AD, 15 subjects with FTD and 10 healthy controls (HC). All subjects undergo physical, biochemical and cognitive screening. In recruited subjects dynamic scanning was performed for 60u2005min after injection on a high-resolution PET scanner, and images were coregistered with 3D T1-weighted MRI. Tracer binding to amyloid was analysed using the cerebellum as the reference region, and comparing data to pooled data from the European Network on Diagnostic Molecular Imaging (DiMI) using the tracer 11C-Pittsburgh compound-B (PIB). Regions of interest were placed in frontal, temporal and parietal neocortical areas. Results To date eight subjects have been studied. Neocortical binding of AV-45 in these subjects is in the same range as observed with PIB. Nonspecific binding to white matter was observed in all subjects. Conclusion Binding of 18F-AV-45 to amyloid in AD has been confirmed, but was absent in FTD and HC. 18F-AV-45 is a promising new PET tracer for the in vivo imaging of amyloid deposition in AD, and the distinction from other forms of dementia.

Plasma metals as potential biomarkers in dementia: a case–control study in patients with sporadic Alzheimer’s disease

Sporadic Alzheimer’s disease (AD) is a neurodegenerative disorder that causes the most prevalent form of age-related dementia but its pathogenesis remains obscure. Altered regulation of metals, particularly pan-cerebral copper deficiency, and more regionally-localized perturbation of other metals, are prominent in AD brain although data on how these CNS perturbations are reflected in the peripheral bloodstream are inconsistent to date. To assess the potential use of metal dysregulation to generate biomarkers in AD, we performed a case–control study of seven essential metals and selenium, measured by inductively coupled plasma mass-spectrometry, in samples from AD and matched control cases. Metals were sodium, potassium, calcium, magnesium, iron, zinc, and copper. In the whole study-group and in female participants, plasma metal levels did not differ between cases and controls. In males by contrast, there was moderate evidence that zinc levels trended towards increase in AD [10.8 (10.2–11.5)]xa0µmol/L, mean (±u200995% CI; Pu2009=u20090.021) compared with controls [10.2 (9.6–10.4)]. Thus alterations in plasma zinc levels differed between genders in AD. In correlational analysis, there was evidence for an increased number of ‘strong’ metal co-regulations in AD cases and differential co-modulations of metal pairs: copper-sodium (Rcontrolu2009=u2009−u20090.03, RADu2009=u20090.65; Pu2009=u20090.009), and copper-calcium (Rcontrolu2009=u2009−u20090.01, RADu2009=u20090.65; Pu2009=u20090.01) were significant in AD males, potentially consistent with reported evidence for dysregulation of copper in severely damaged brain regions in AD. In conclusion, our data suggest that the measurement of metals co-regulation in plasma may provide a useful representation of those metal perturbations taking place in the AD brain and therefore might be useful as plasma-based biomarkers.Graphical Abstract

A POSITRON EMISSION TOMOGRAPHY STUDY OF [18F]–FLORBETAPIR IN ALZHEIMER'S DISEASE AND FRONTOTEMPORAL DEMENTIA

Background Deposits of fibrillar amyloid β (Aβ) protein are important in the pathophysiology of Alzheimers disease (AD), but not in frontotemporal dementia (FTD). In vivo imaging of Aβ protein deposition, therefore, is a promising tool in the differential diagnosis of dementia syndromes. Previous pathological and imaging studies suggest that a minority of FTD patients may have coexistent Aβ deposition, possibly due to possession of the apolipoprotein E (APOE) ε4 allele. We report a PET study using the novel Aβ ligand [18F]–florbetapir in patients with AD, FTD and healthy controls. Methods Ten healthy controls (mean age 62.5±5.2, MMSE 30), 10 AD patients (mean age 62.6±4.5 years, MMSE 10–24) and eight FTD patients (mean age 62.5±9.6, MMSE 0–30) were recruited to the study. All patients underwent detailed clinical and neuropsychological assessment, and were genotyped for APOE status. All participants underwent imaging with [18F]–florbetapir using the high–resolution research tomograph, and FTD patients also underwent [18F]–fluorodeoxyglucose (FDG) PET. Motion–corrected static florbetapir PET images (50–60 minutes post–injection) were coregistered with 3T volumetric T1–weighted MR images. Grey matter uptake values, intensity–normalised to the mean grey matter cerebellar uptake, were sampled from cortical and subcortical areas using a probabilistic anatomical atlas. Group differences were analysed using non–parametric Kruskal–Wallis test. Results Total cortical grey matter florbetapir uptake values were significantly higher in AD (mean uptake ratio 1.77±0.38) compared to FTD patients (1.25±0.36, p=0.002) and controls (1.29±0.11, p=0.04). Florbetapir uptake was also higher in AD in frontal, parietal, occipital and central subcortical regions. PET images of seven of the FTD patients were visually classed as amyloid negative. One FTD patient (homozygous for APOE ε4) displayed high cortical florbetapir retention, with prominent mesiofrontal hypometabolism on FDG PET consistent with the clinical diagnosis. Three AD patients were APOE ε4 homozygous, while three AD and three FTD patients were ε3/4 heterozygotes. APOE ε4 gene dosage did not appear to be directly related to amyloid load. Discussion Imaging amyloid deposition with [18F]–florbetapir in dementia contributes to differential diagnosis between AD and non–amyloid diseases such as FTD. Our findings are in line with previous reports of coexistent amyloid deposition in a small number of FTD patients. Florbetapir imaging will be of particular interest in subjects with progressive cognitive deficits that are difficult to classify clinically.

[18F]-Florbetapir PET distinguishes Frontotemporal Dementia from Alzheimer's Disease.

Frontotemporal dementia (FTD) is a clinical syndrome with a heterogeneous molecular basis. The genetics of FTD has been one of the success stories in genetics over the past 15 years. Classic family based linkage studies have identified genes that explain a large part of the families with a Mendelian inheritance of the disease. This group of familial FTD patients has now been linked to mutations in several genes, including the microtubule-associated protein tau (MAPT), progranulin (GRN), valosin-containing protein (VCP), charged multivescicular body protein 2B (CHMP2B), TAR DNA-binding protein 43 (TDP43) and Fused in Sarcoma (FUS) and most recently C9Orf72. Over the years the identified genes have triggered many studies that increased our understanding of the disease process. Neuropathologically the disease can be divided in two major groups that have a clear correlation with their genetic background; hose with tau-positive inclusions and those with ubiquitin-positive and TDP43 positive inclusions. The field of genetics keeps changing rapidly thanks to technological developments, first with the development of Genome Wide Association Studies (GWAS) studies but now also with the use of next generation sequencing, as was already demonstrated with the identification of the expanded repeat in C9Orf72, and we can also expect many whole exome or whole genome sequencing studies. This review provides an overview of the genetics of FTD, with an update of recent discoveries.

Plasma alkaline phosphatase inversely correlates with cognitive function in Alzheimer's disease

prospective information on the incidence of dementia after anaesthesia and surgery because most studies measure cognition before and after surgery using neuropsychological tests without specifically assessing dementia using an appropriate functional measurement tool. Methods: At one year, we analyzed the results of patients enrolled in the Anaesthesia Cognition Evaluation (ACE) Study. This study is designed to assess cognition and function in patients over 60 yrs, scheduled to undergo elective total hip joint replacement (THJR) surgery for osteoarthritis. Patients were assessed pre-operatively and at 3 and 12 months post operatively The Mini Mental State Examination (MMSE) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) were used to infer risk of dementia. Patients at risk for dementia were identified using the Demegraph which plots the MMSE score against the IQCODE score, and has been shown to be accurate in predicting patients at risk of dementia. Results: To date, 27 patients have been tested one year after surgery. Four patients (14.8%) are at risk of dementia as indicated by the demegraph. This is far in excess of the expected rate of 0.30.8%. Conclusions: Although POCD is well recognized in the elderly after anaesthesia and surgery, the incidence of dementia may also be increased following these interventions. The implications of this are profound because patients over the age of 60 receive a third of all anaesthetics (over a million each year in Australia).