Anxiety and behavioural disturbance as markers of prodromal Alzheimer's disease in patients with mild cognitive impairment.

BACKGROUND: Depression and anxiety have been reported to be independently predictive of conversion to Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI). Anxiety symptoms have been less well studied and findings in this regard have been inconsistent. The objectives of this study are to determine which symptoms among a range of neuropsychiatric symptoms known to commonly occur in patients with MCI are predictive of later conversion to AD. We also wish to determine whether these symptoms track existing measures of declining cognitive and functional status or may be considered distinct and sensitive biomarkers of evolving Alzheimer's pathology. METHODS: One hundred and sixty-one patients with MCI were identified from consecutive referrals to a memory clinic. Univariate, multivariate and cox regression analyses were conducted. RESULTS: Seventy-six per cent of all patients had at least one neuropsychiatric symptom at baseline of which anxiety (52%), affective disturbance (37%) and aggression (32%) were the most common. Increasing symptom frequency was observed with increasing clinical severity. Anticipatory anxiety and activity disturbances were significantly associated with earlier conversion to AD although this association did not remain significant following adjustment for cognitive status at baseline. CONCLUSION: Neuropsychiatric symptoms and anxiety symptoms in particular are common in patients with MCI. In this sample anxiety for upcoming events and purposeless activity frequently co-occurred and were significant clinical predictors of earlier conversion to AD. However, these findings were not independent of cognitive status at baseline and therefore may be markers of severity rather than independent predictors of disease progression.

Detecting prodromal Alzheimer's disease in mild cognitive impairment: utility of the CAMCOG and other neuropsychological predictors.

BACKGROUND: The Cambridge cognitive examination (CAMCOG) is a mini neuropsychological battery which is well established and widely used. The utility of the CAMCOG in detecting prodromal Alzheimer's disease (AD) in patients with mild cognitive impairment (MCI) has not been determined. The objectives of this study are: to establish which subtests of cognitive domains contained within the CAMCOG are predictive of conversion to AD, to compare these with an extended version of the delayed word recall (DWR) test and to establish optimal cut points for all measures used. METHODS: 182 patients with MCI were identified from consecutive referrals to a memory clinic. Logistic regression, cox regression and receiver operating characteristic curve (ROC) analyses were conducted. RESULTS: The DWR displayed the best sensitivity (77%) and specificity (76%). The composite memory score contained within the CAMCOG achieved similar sensitivity (78%) and specificity (74%). The recognition component of the extended DWR demonstrated good specificity (85%) but poor sensitivity (57%). The optimal predictive model combined category fluency with the DWR and achieved predictive accuracy of 83%. CONCLUSION: The DWR, which is a test specifically designed to have high predictive accuracy for AD, performed best. The composite measure of memory contained within the CAMCOG performed similarly well. The DWR has the advantage of being brief, easy to administer and suitable for use in non-specialist settings. The CAMCOG takes longer to administer but provides information regarding additional cognitive domains and is sensitive to change over time. Category fluency may be usefully combined with the DWR to improve predictive accuracy.

Noradrenaline acting on astrocytic ß2-adrenoceptors induces neurite outgrowth in primary cortical neurons.

The neurotransmitter noradrenaline (NA) has anti-inflammatory properties and promotes expression of neurotrophic factors in the central nervous system (CNS) via activation of glial adrenoceptors. Here we examined the ability of conditioned media (CM) from NA-treated glial cells to impact upon neuronal complexity. Primary rat cortical neurons were treated either directly with NA (1-10 µM), or treated with CM from NA-stimulated primary mixed glial cells. Neuronal complexity was assessed using Sholl analysis. Exposure of neurons to CM from NA-stimulated glial cells increased all indices of neuronal complexity, whereas direct exposure of neurons to NA did not. CM from NA-stimulated astrocytes, but not microglia, also increased neuronal complexity indicating a key role for astrocytes. The ß-adrenergic subtype was implicated in this response as the increase was blocked by the ß-adrenoceptor antagonist propanolol, but not by the α-adrenoceptor antagonist phentolamine. CM from glial cells treated with the ß2-adrenoceptor agonists salmeterol and clenbuterol, but not the ß1-adrenoceptor agonist xamoterol, mimicked the ability of NA to increase neuronal complexity. NA induced expression of a range of growth factors (BDNF, NGF-ß, GDNF, FGF-2 and IL-6) in glial cells. In addition to this, the phosphatidylinositol 3-kinase (PI3K), mitogen activated protein kinase (MAPK) and JAK-STAT signalling pathways are implicated in NA CM-induced neuritic growth as inhibition of these pathways attenuated NA CM-induced neuritic growth. In conclusion, this study indicates a novel role for NA acting at glial ß2-adrenoceptors to induce neuritic growth through the expression of soluble factors that elicit a neurotrophic action and increase neuronal complexity.

Noradrenaline induces IL-1ra and IL-1 type II receptor expression in primary glial cells and protects against IL-1beta-induced neurotoxicity.

The pro-inflammatory cytokine interleukin-1beta (IL-1beta) plays a key role in initiating an immune response within the central nervous system (CNS), and is thought to be a significant contributor to the neurodegenerative process. The actions of IL-1beta can be regulated by interleukin-1 receptor antagonist (IL-1ra), which prevents IL-1beta from acting on the IL-1 type I receptor (IL-1RI). Another negative regulator of the IL-1 system is the IL-1 type II receptor (IL-1RII); a decoy receptor that serves to sequester IL-1. Consequently, pharmacological strategies that tip the balance in favour of IL-1ra and IL-1RII may be of therapeutic benefit. Evidence suggests that the neurotransmitter noradrenaline elicits anti-inflammatory actions in the CNS, and consequently may play an endogenous neuroprotective role. Here we report that noradrenaline induces production of IL-1ra and IL-1RII from primary rat mixed glial cells. In contrast, noradrenaline did not alter IL-1beta expression, or expression of IL-1RI or the IL-1 type I receptor accessory protein (IL-1RAcp); both of which are required for IL-1 signalling. Our results demonstrate that the ability of noradrenaline to induce IL-1ra and IL-1RII is mediated via beta-adrenoceptor activation and downstream activation of protein kinase A and extracellular signal-regulated kinase (ERK). In parallel with its ability to increase IL-1ra and IL-1RII, noradrenaline prevented neurotoxicity in cortical primary neurons induced by conditioned medium from IL-1beta treated mixed glial cells. These data indicate that noradrenaline negatively regulates IL-1 system in glial cells and has neuroprotective properties in situations where IL-1 contributes to pathology.

The virtual haptic display: a device for exploring 2-D virtual shapes in the tactile modality.

In order to understand better the processes involved in the perception of shape through touch, someelement of control is required over the nature of the shape presented to the hand and the presentation timing. To that end, we have developed a cost-effective, computer-controlled apparatus for presenting haptic stimuli using active touch, known as a virtual haptic display (VHD). The operational principle behind this device is that it translates black and white visual images into topographic, 2-D taxel (tactile pixel) arrays, along the same principle using in Braille letters. These taxels are either elevated or depressed at any one time representing white and black pixel colors of the visual image, respectively. To feel the taxels, the participant places their fingers onto a carriage which can be moved over the surface of the device to reveal a virtual shape. We conducted two experiments and the results show that untrained participants are able to recognize different, simple and complex, shapes using this apparatus. The VHD apparatus is therefore ideal at presenting 2-Dshapes through touch alone. Moreover,this device and its supporting software can also be used for presenting computer-controlled stimuli in cross-modal experiments.

Eicosapentaenoic acid confers neuroprotection in the amyloid-beta challenged aged hippocampus.

Among the changes that occur in the hippocampus with age, is a deficit in long-term potentiation (LTP). This impairment is associated with inflammatory changes, which are typified by increased concentration of the pro-inflammatory cytokine interleukin-1beta (IL-1beta). Activated microglia are the most likely cell source of IL-1beta, but data demonstrating an age-related increase in microglial activation is equivocal. Here we demonstrate that the age-related deficit in LTP is accompanied by increased expression of cell surface markers of activated microglia (major histocompatibility complex II and CD40) and increased IL-1beta production, and that these changes may be stimulated by interferon-gamma. Treatment of aged rats with eicosapentaenoic acid (EPA) attenuates these changes and we suggest that IL-4 mediates the action of EPA. We demonstrate that aged rats exhibit an exaggerated response to intracerebroventricular injection of beta-amyloid peptide 1-40 (Abeta). Thus Abeta inhibited LTP in aged, but not young, rats and induced a further increase in hippocampal IL-1beta concentration. Of particular significance is the demonstration that EPA protects the aged brain so that the increased vulnerability to Abeta is ameliorated in EPA-treated rats.