The use of neuroimaging in dementia by Irish general practitioners.

BACKGROUND: More than 48,000 people in Ireland are living with dementia, and the number is likely to rise to 130,000 by 2041. Dementia frequently remains undiagnosed, depriving many of early interventions and the opportunity to plan for the future. Neuroimaging is helpful in the diagnosis of dementia, yet it is often insufficiently utilised. General practitioners (GPs) often decide which patients should be referred on for specialist assessment and as such play a crucial role in dementia diagnosis. AIMS: To establish the accessibility of neuroimaging in dementia by GPs, current referral patterns, confidence in referral and opinions on radiology reports. METHODS: The research design was a postal survey among GPs in single and group practices in urban, rural and semi-rural areas in the east and southeast of Ireland. GPs were identified from the Irish Medical Directory and posted individual anonymous questionnaires. RESULTS: A third of participants reported that they had no direct access to neuroimaging. Access differed between public and private patients. GPs primarily referred to computed tomography and magnetic resonance imaging, but only 14.6 % based these referrals on published guidelines. A total of 47.8 % of participants were not very confident in their ability to choose the most appropriate modality. CONCLUSION: Access to neuroimaging investigations for suspected cases of dementia varies between locations and public and private systems. To improve diagnostic rates and ensure appropriate utilisation of imaging resources, GPs require access to clinical and referral guidelines to ensure appropriate use of neuroimaging and the best possible patient outcomes.

Quantitative spectroscopic imaging with in situ measurements of tissue water T1, T2, and density.

The use of tissue water as a concentration standard in proton magnetic resonance spectroscopy ((1)H-MRS) of the brain requires that the water proton signal be adjusted for relaxation and partial volume effects. While single voxel (1)H-MRS studies have often included measurements of water proton T(1), T(2), and density based on additional (1)H-MRS acquisitions (e.g., at multiple echo or repetition times), this approach is not practical for (1)H-MRS imaging ((1)H-MRSI). In this report we demonstrate a method for using in situ measurements of water T(1), T(2), and density to calculate metabolite concentrations from (1)H-MRSI data. The relaxation and density data are coregistered with the (1)H-MRSI data and provide detailed information on the water signal appropriate to the individual subject and tissue region. We present data from both healthy subjects and a subject with brain lesions, underscoring the importance of water parameter measurements on a subject-by-subject and voxel-by-voxel basis.

Mitochondrial function in physically active elders with sarcopenia.

Physical activity is reported to protect against sarcopenia and preserve mitochondrial function. Healthy normal lean (NL: n=15) and sarcopenic (SS: n=9) participants were recruited based on body composition (DXA, Lunar DPX), age, and physical activity. Gastrocnemius mitochondrial function was assessed by (31)P MRS using steady-state exercise in a 4T Bruker Biospin. Total work (429.3+/-160.2J vs. 851.0+/-211.7J, p<0.001) and muscle volume (p=0.006) were lower in SS, although these variables were not correlated (NL r=-0.31, p=0.33, SS r=(0.03, p=0.93). In the SS resting ATP/ADP was lower (p=0.03) and ATP hydrolysis higher (p=0.02) at rest. Free energy ATP hydrolysis was greater at the end of exercise (p=0.02) and [ADP] relative to total work output was higher in SS (ANCOVA, p=0.005). [PCr] recovery kinetics were not different between the groups. Adjusting these parameters for differences in total work output and muscle volume did not explain these findings. These data suggest that aerobic metabolism in physically active older adults with sarcopenia is mildly impaired at rest and during modest levels of exercise where acidosis was avoided. Muscle energetics is coordinated at multiple cellular levels and further studies are needed to determine the loci/locus of energy instability in sarcopenia.

Closed-head minimal traumatic brain injury produces long-term cognitive deficits in mice.

Victims of minimal traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study we adopted a non-invasive closed-head weight-drop mouse model to produce mTBI. We examined the effects of 20, 25, or 30 g weight drop 7, 30, 60 and 90 days following injury on mice's ability to perform the Morris water maze. The mice suffered profound long-lasting learning and memory deficits that were force- and time-dependent. Although the injured mice could acquire the task, they could not improve their initial escape latency by more than 50%, while normal mice improved by up to 450% (P<0.001). In order to directly compare the learning ability of individual mice following our mTBI we have devised a new measure which we term learning rate. We define learning rate as the rate the mouse improved its own performance in consecutive trials in a given experimental day. The learning rate of control mice increased linearly throughout the testing period with a slope of approximately 0.9. Injured mice that sustained 20 and 25 g weight drop could also improve their learning rate linearly but with a slope of only 0.2. Mice who sustained 30 g weight drop could not improve their learning rate linearly and reached a plateau after the third experimental learning day. These results indicate that the severity of injury may correlate with the degree of integration of the learning task. These cognitive deficits occurred without any other clear neurological damage, no evident brain edema, no notable damage to the blood-brain barrier and no early anatomical changes to the brain (observed by magnetic resonance imaging imaging). These results demonstrate that persistent deficits of cognitive learning abilities in mice, similar to those observed in human post-concussive syndrome, can follow mTBI without any anatomical damage to the brain and its surrounding tissue.

Small shifts in craniotomy position in the lateral fluid percussion injury model are associated with differential lesion development.

Previous studies have shown that location and direction of injury may affect outcome in experimental models of traumatic brain injury. Significant variability in outcome data has also been noted in studies using the lateral fluid percussion brain injury model (FPI) in rats. In recent studies from our laboratory, we observed considerable variability in localization and severity of tissue damage as a function of small changes in craniotomy position. To further address this issue, we examined the relationship between craniotomy position and brain lesion size/location in rats subjected to moderate FPI (2.28 +/- 0.18 atmospheres). With placement of a 5-mm craniotomy adjacent to the sagittal suture, there was both ipsilateral and contralateral damage as detected at 3 weeks posttrauma using T2-weighted magnetic resonance imaging (MRI). The MRI lesions were generally restricted to the hippocampus and subcortical layers. Shifting of the craniotomy site laterally was associated with increased ipsilateral tissue damage and a greater cortical component that correlated with distance from the sagittal suture. In contrast, the contralateral MRI lesion did not change significantly in size or location unless the center of the craniotomy was placed more than 3.5 mm from the sagittal suture, under which condition contralateral damage could no longer be detected. Ipsilateral tissue damage as determined from the MRI scans was linearly correlated to motor outcome but not with cognitive outcome as assessed by the Morris Water Maze. We conclude that craniotomy position is critical in determining extent and location of tissue injury produced during the lateral FPI model in rats. Addressing such potential variability is essential for studies that address either injury mechanisms or therapeutic treatments.

Presence of DNA fragmentation and lack of neuroprotective effect in DFF45 knockout mice subjected to traumatic brain injury.

BACKGROUND: Apoptosis plays an important pathophysiologic role in neuronal cell loss and associated neurologic deficits following traumatic brain injury (TBI). DNA fragmentation represents one of the characteristic biochemical features of neuronal apoptosis and is observed after experimental TBI. DFF45 and DFF40 are essential for DNA fragmentation in various models of apoptosis. MATERIALS AND METHODS: We used mice deficient in DFF45 and wild-type controls. Oligonucleosomal DNA fragmentation induced by TBI was analyzed using in vivo and in vitro assays. Expression and integrity of DFF45 and DFF40 proteins was assessed by Western analysis. Other outcome measurements included neurologic scoring, learning/memory tests, lesion volume measurements (MRI), and assessment of cell viability in vitro among others. RESULTS: We compared the effects of controlled cortical impact (CCI) trauma in DFF45 knockout mice and wild-type controls. Analysis of TBI-induced DNA fragmentation in brain cortex from wild-type and DFF45 knockout mice indicates that, although somewhat delayed, oligonucleosomal cleavage of DNA occurs after TBI in DFF45 knockout mice. DFF45 knockouts showed no significant differences in behavioral outcomes or lesion volumes after TBI as compared to wild-type controls. Using an in vitro reconstitution system, we also demonstrated that cleavage of DFF45 by caspase-3 is not sufficient for DNA fragmentation induced by protein extracts from rat brain cortex. We found that endonuclease activity induced in rat brain cortex following TBI depends on the presence of Mg2+ and Ca2+, but is not inhibited by Zn2+. Primary neuronal cultures from DFF45 knockouts failed to show DNA laddering in response to staurosporine, but did show prominent, albeit delayed, DNA fragmentation following treatment with etoposide. In contrast, primary neurons from wild-type animals demonstrated marked DNA fragmentation following treatment with staurosporine or etoposide. CONCLUSIONS: The results of this study suggest that, in addition to DFF45/40, other endonucleases may be essential for chromatin degradation during neuronal apoptosis in adult brain after TBI.

Ischaemic preconditioning in the rat brain: a longitudinal magnetic resonance imaging (MRI) study.

Ischaemic preconditioning in rats was studied using MRI. Ischaemic preconditioning was induced, using an intraluminal filament method, by 30 min middle cerebral artery occlusion (MCAO), and imaged 24 h later. The secondary insult of 100 min MCAO was induced 3 days following preconditioning and imaged 24 and 72 h later. Twenty-four hours following ischaemic preconditioning most rats showed small sub-cortical hyperintense regions not seen in sham-preconditioned rats. Twenty-four hours and 72 h following the secondary insult preconditioned animals showed significantly smaller lesions (24 h = 112 +/- 31 mm(3), mean +/- standard error; 72 h = 80 +/- 35 mm(3)), which were confined to the striatum, than controls (24 h = 234 +/- 32 mm(3), p = 0.026; 72 h = 275 +/- 37 mm(3), p = 0.003). In addition during lesion maturation from 24 to 72 h post-secondary MCAO, preconditioned rats displayed an average reduction in lesion size as measured by MRI whereas sham-preconditioned rats displayed increases in lesion size; this is the first report of such differential lesion volume evolution in cerebral ischaemic preconditioning.

Selective blockade of the mGluR1 receptor reduces traumatic neuronal injury in vitro and improvesoOutcome after brain trauma.

The effects of selective blockade of group I metabotropic glutamate receptor subtype 1 (mGluR1) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. The selective mGluR1 antagonists (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), and (S)-(+)-alpha-amino-4-carboxy-2-methylbezeneacetic acid (LY367385) provided significant neuroprotection in rat cortical neuronal cultures subjected to mechanical injury, in both pretreatment or posttreatment paradigms. Administration of the antagonists also attenuated glutamate-induced neuronal cell death in the cultures. Coapplication of these antagonists with the N-methyl-d-aspartate (NMDA) receptor antagonist (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801) had additive neuroprotective effects in glutamate injured cultures. Intracerebroventricular administration of AIDA to rats markedly improved recovery from motor dysfunction after lateral fluid percussion induced traumatic brain injury (TBI). Treatment with mGluR1 antagonists also significantly reduced lesion volumes in rats after TBI, as evaluated by MRI. It appears that these compounds mediate their neuroprotective effect through an mGluR1 antagonist action, as demonstrated by inhibition of agonist induced phosphoinositide hydrolysis in our in vitro system. Moreover, AIDA, CPCCOEt, and LY367385, at concentrations shown to be neuroprotective, had no significant effects on the steady state NMDA evoked whole cell current. Taken together, these data suggest that modulation of mGluR1 activity may have substantial therapeutic potential in brain injury.

mGluR5 antagonists 2-methyl-6-(phenylethynyl)-pyridine and (E)-2-methyl-6-(2-phenylethenyl)-pyridine reduce traumatic neuronal injury in vitro and in vivo by antagonizing N-methyl-D-aspartate receptors.

The effect of selective group I metabotropic glutamate receptor subtype 5 (mGluR5) antagonists 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and (E)-2-methyl-6-(2-phenylethenyl)-pyridine (SIB-1893) on neuronal cell survival and post-traumatic recovery was examined using rat in vitro and in vivo trauma models. Treatment with MPEP and SIB-1893 showed significant neuroprotective effects in rat cortical neuronal cultures subjected to mechanical injury. Application of the antagonists also attenuated glutamate- and N-methyl-D-aspartate (NMDA)-induced neuronal cell death in vitro. Intracerebroventricular administration of MPEP to rats markedly improved motor recovery and reduced deficits of spatial learning after lateral fluid percussion-induced traumatic brain injury. Lesion volumes as assessed by magnetic resonance imaging were also substantially reduced by MPEP treatment. Although we show that MPEP acts as a potent mGluR5 antagonist in our culture system, where it completely blocks agonist-induced phosphoinositide hydrolysis, electrophysiological and pharmacological studies indicate that MPEP and SIB-1893 also inhibit NMDA receptor activity at higher concentrations that are neuroprotective. Taken together, these data suggest that MPEP and SIB-1893 may have therapeutic potential in brain injury, although the mechanisms of neuroprotective action for these drugs may reflect their ability to modulate NMDA receptor activity.

The effect of sample freezing on proton magic-angle spinning NMR spectra of biological tissue.

Magic-angle spinning (MAS) has recently been shown to enhance spectral resolution in NMR examinations of intact biological tissue ex vivo. This work demonstrates that freezing certain tissue samples before examination by 1H MAS NMR can have a marked effect on their spectra. Spectra of rat kidney after freezing in liquid nitrogen, compared with spectra before freezing, showed a significant increase in signal intensities from alanine (>100%), glutamine (>40%), and glycine (>100%), and a decrease in signals assigned to lipids and other macromolecules. Some resonances--such as from leucine, valine, isoleucine, and aspartate--only became visible after freezing the tissue. These observations suggest that low temperature storage of tissue necropsies or biopsies might affect the results of a MAS NMR analysis, possibly resulting in the misinterpretation of metabolite changes to pathogen or disease effects.

Chronic alcohol exposure decreases brain intracellular free magnesium concentration in rats.

Phosphorus magnetic resonance spectroscopy was used to determine effects of acute and chronic alcohol exposure on brain intracellular free magnesium concentration (Mgf) and bioenergetic state in rats. Acute alcohol (3 mg kg-1, i.p.) resulted in a transient ( < 2h) decline in brain Mgf and cytosolic phosphorylation ratio, and an increase in mitochondrial oxidative capacity. In contrast, chronic exposure to alcohol for 30 days by vapour inhalation resulted in a depletion of brain Mgf with no significant change in bioenergetic parameters. Subsequent exposure of chronically alcoholised rats to an acute dose of alcohol (3 g kg-1) did not result in any further changes. We conclude that chronic exposure to alcohol results in a depletion of brain Mgf and compromised bioenergetic regulation.

Peer review of utilisation of medical beds at Flinders Medical Centre.

A clinical audit of all medical inpatients was undertaken and the appropriateness of admissions and of length of stay was assessed from a clinical viewpoint on 4 separate days within an 11 day period. In addition, the mode of entry of hospital, length of stay of patients, occupancy rate, and the vacancy interval were analysed for all medical patients during the preceding three months. The mean length of stay of medical patients in hospital during this 3 months period was 5.6 days, with an occupancy rate of 93% and a vacancy interval of 0.43 days. Seventy-four percent of all medical inpatients were admitted through the Accident and Emergency Department (A&E). The short length of stay, high occupancy rate and low vacancy interval indicated that bed usage in the medical wards was efficient. A total of 493 reviews was carried out on 294 individual patients. In 87% of cases, both admission to hospital and length of stay were appropriate on clinical grounds alone. The number of patients whose admission to hospital (11), or length of stay (27) was not justified on medical grounds alone was 38 (13% of total patients). These patients were elderly, or had complex social and psychological problems contributing to their illness. It was concluded that stricter control of admissions or length of stay was unlikely to make a significant numbers of beds available for other admissions.