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Biomedical subjects

G K Wilcock

Publications and source records attributed to G K Wilcock.

At least 19 recordsLinked to original sources
PubMed2006

How are quality of life ratings made? Toward a model of quality of life in people with dementia.

Quality of life (QOL) has become a focus of research in dementia. In measuring QOL, the views of people with dementia often have not been considered as researchers have proposed that they may not be able to articulate their opinions. This paper counters this belief, presenting a study using a grounded theory methodology to explore the issues that people with dementia felt were important for their QOL. Further, we propose a model of QOL including hypothesised links between important issues (including family and health), QOL and other variables. Twenty-five participants took part in one of nine focus groups. The groups included participants with mild to severe dementia with ages ranging from 49 to 93 years. Results indicate that most of the participants were willing and able to talk about their QOL. Of the 25 participants, only two said that their cognitive problems affected their QOL. Twenty-two issues were discovered through analysis to contribute to QOL, including continuingto live in your own home, independence, spouse and other family, feeling happy and feeling useful. People with dementia used social comparisons in talking about their QOL, as well as direct evaluation of their own happiness. A model of QOL based on theories of coping and response shift is suggested. The fact that so few of the participants talked about disease-orientated issues challenges the large cognitive components included in many QOL measures for use with people with dementia.

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PubMed2005

Relationship of neurofibrillary pathology to cerebral amyloid angiopathy in Alzheimer's disease.

Over 90% of patients with Alzheimer's disease (AD) develop cerebral amyloid angiopathy (CAA). Severe dyshoric CAA, in which amyloid extends into the surrounding brain parenchyma, may be associated with adjacent clustering of tau-immunopositive neurites but the relationship of CAA to neurofibrillary pathology has not been systematically investigated. In the present study this relationship was examined in sections of frontal, temporal and parietal cortex from 25 AD patients with moderate to severe CAA and 26 with mild or absent CAA. We measured immunolabelling of abnormally phosphorylated tau adjacent to A beta-laden and non-A beta-laden arteries and arterioles, and in cortex away from arteries and arterioles. We also analysed the possible influence of APOE genotype on these measurements. There were no significant differences between the lobes in measurements of tau labelling, either around blood vessels or elsewhere in the cortex. However, tau labelling around A beta-laden arteries and arterioles significantly exceeded that around non-A beta-laden blood vessels (P<0.001) and this, in turn was greater than the labelling of cortex away from blood vessels (P<0.001). There was no association between APOE epsilon 4 and the immunolabelling density for tau, whether around amyloid- or non-amyloid-laden arteries and arterioles, or in the cerebral cortex away from these. We propose that both CAA and peri-vascular accumulation of hyperphosphorylated tau may be a consequence of elevated levels of soluble A beta around cortical arteries and arterioles.

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PubMed2003

APOE epsilon 4 influences the pathological phenotype of Alzheimer's disease by favouring cerebrovascular over parenchymal accumulation of A beta protein.

The relative amounts of amyloid beta-protein (A beta) in cerebral blood vessels and parenchyma vary considerably amongst patients with Alzheimer's disease (AD). Although several mechanisms have been proposed to explain this variability, the underlying genetic and environmental determinants are still unclear, as are the functional consequences. Polymorphisms in APOE, the gene for apolipoprotein E (ApoE), influence the risk of developing AD and of deposition of A beta within the brain. We examined the relationship between the APOE genotype and the relative extent of accumulation of A beta as plaques within the cerebral parenchyma and in cortical blood vessels in the form of cerebral amyloid angiopathy (CAA), in autopsy brain tissue from 125 AD cases and from 53 elderly, neurologically normal controls of which 19 had CAA without other neuropathological features of AD. In the AD cases, we also assessed whether the severity of CAA was related to the age of onset and duration of dementia, risk factors for atherosclerotic vascular disease, and histologically demonstrable cerebral infarcts or foci of haemorrhage. The APOE genotype was determined by a standard polymerase chain reaction-based method. Paraffin sections of frontal, temporal and parietal lobes were immunolabelled for A beta and the parenchymal A beta load (total A beta minus vessel-associated A beta) was quantified by computer-assisted image analysis. CAA severity was scored for cortical and leptomeningeal vessels. The relevant clinical data were obtained from the database of the South West Brain Bank. In AD, we found the severity of CAA to be strongly associated with the number of epsilon 4 alleles (P < 0.0001) but the parenchymal A beta load to be independent of APOE genotype. Cases with severe CAA had a lower parenchymal A beta load than had those with moderate CAA (P = 0.003). Neither the severity of CAA nor the parenchymal A beta load correlated with age of onset, duration of disease or age at death, and the severity of CAA also did not correlate with the presence of cerebral infarcts or foci of haemorrhage. These findings indicate that possession of the APOE epsilon 4 allele favours vascular over parenchymal accumulation of A beta in AD. This may influence the pathogenesis of neurodegeneration in epsilon 4-associated AD.

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PubMed2002

Age-related changes in the preattentional detection of visual change.

The ability to detect changes in the environment which occur outside the focus of current awareness is essential if the individual is to be able to divert attention to biologically salient stimuli. The preattentional mechanism underlying the automatic detection of stimulus change in the auditory modality has been extensively studied by recording an event-related potential known as the mismatch negativity. Recently a homologous response from the visual cortex has also been described. Ageing has been shown to affect the efficiency of preattentional processing in the auditory modality, a factor which may contribute to cognitive changes in the elderly. It is unclear whether a similar effect occurs in the visual system. To investigate this issue the visual mismatch negativity was recorded from 12 older adults and 24 younger adults. Whereas the younger adults displayed a robust visual MMN, that evoked in the older adults was significantly reduced in amplitude. The results are indicative of age-related deficits in automatic visual processing.

Adult↗
PubMed2002

The effect of selegiline in the treatment of people with Alzheimer's disease: a meta-analysis of published trials.

OBJECTIVE: To evaluate the effect of selegiline in the treatment of patients with Alzheimer's disease, in terms of cognitive performance, functional ability, emotional state (including behaviour and mood) and global response. Data Sources The Cochrane database of trials, Embase, Medline and Psychlit. Study Selection Unconfounded, double-blind, randomised trials of selegiline compared with placebo reported before 31 December 1998. Data Extraction The reviewers selected trials for inclusion. Individual patient data were sought, but when these could not be retrieved summary data were extracted from published papers. RESULTS: Of 27 identified trials, 14 met the inclusion criteria. Individual patient data were retrieved from eight trials on 821 patients. Summary data were extracted from five trials on 240 patients. No data were available from one trial on 12 patients, which was therefore excluded from the meta-analysis. Fixed and random effects meta-analyses were performed on standardised mean differences. For cognition there was a statistically significant difference between selegiline and placebo at 4-6 weeks and 8-17 weeks after randomisation (at 8-17 weeks: smd=0.45 [95% confidence interval 0.03 to 0.88]), but this disappeared at later assessments. The size of the treatment difference was considered unlikely to be of clinical importance. Although there was a statistically significant difference at 4-6 weeks for activities of daily living, this disappeared at later assessments (at 8-17 weeks: smd=0.33 [-0.33, 0.69]). There were no statistically significant differences or clinically relevant differences between selegiline and placebo in terms of emotional state or global response. CONCLUSION: Although there was some evidence of improvement with selegiline in the short term in cognition and activities of daily living, the magnitude of the effect did not reach clinical importance. There was no evidence of long term effects.

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PubMed2001

Identification and structure of the nerve growth factor binding site on TrkA.

Nerve growth factor (NGF) is involved in the development and maintenance of the nervous system and has been implicated as a possible therapeutic target molecule in a number of neurodegenerative diseases, especially Alzheimer's disease. NGF binds with high affinity to the extracellular region of a tyrosine kinase receptor, TrkA, which comprises three leucine-rich motifs (LRMs), flanked by two cysteine-rich clusters, followed by two immunoglobulin-like (Ig-like) domains. We have expressed the second Ig-like domain as a recombinant protein in E. coli and demonstrate that NGF binds to this domain with similar affinity to the native receptor. This domain (TrkAIg(2)) has the ability to sequester NGF in vitro, preventing NGF-induced neurite outgrowth, and in vivo, inhibiting NGF-induced plasma extravasation. We also present the three-dimensional structure of the TrkAIg(2) domain in a new crystal form, refined to 2.0 A resolution.

Animals↗
PubMed2001

Recombinant human nerve growth factor for clinical trials: protein expression, purification, stability and characterisation of binding to infusion pumps.

Nerve growth factor (NGF) has been suggested to be of therapeutic benefit to patients with Alzheimer's disease. One of the early changes in this disease is a loss of cholinergic function within the brain, and NGF is able to rescue cholinergic neurons both in vitro and in vivo. We describe the production of recombinant human beta-NGF (rhNGF), using baculovirus infection of insect cells; its purification, formulation and subsequent stability for use in clinical trials. Tests were also carried out to monitor release of protein from infusion pumps and catheters for intracerebroventricular administration (icv). Initial problems with non-specific binding were overcome using a blocking formula.

Animals↗
PubMed2001

Accumulation of calbindin in cortical pyramidal cells with ageing; a putative protective mechanism which fails in Alzheimer's disease.

There is considerable interest in the status of calbindin immunoreactive neurones in Alzheimer's disease (AD) but previous studies have produced widely differing results. Here we describe calbindin neurones in temporal neocortex from 18 severely demented patients with neuropathologically confirmed AD and 13 age and post-mortem delay matched, neurologically normal controls. Calbindin immunoreactive neurones were small and round in layers II-IV, and pyramidal in layers IIIc and V. There were significantly more calbindin positive neurones in controls than in AD (mean+/- SD, for each comparison P < 0.01): superior temporal lobe, AD = 3.32 +/- 2.24, Control (C) = 24.83 +/- 10.8; middle temporal lobe, AD = 3.6 +/- 4.94, C = 26.09 +/- 15.7; inferior temporal lobe, AD 3.69 +/- 3.6, C = 25.25 +/- 16.9. Furthermore, there was an age-related increase in immunopositive neurones in the superior (r2 = 0.37, P = 0.046) and inferior (r2 = 0.75, P = 0.01) temporal gyri in controls. In AD the number of calbindin positive neurones did not change with age. This is the first report of such an age-related increase in controls, and it suggests that this, rather than a decrease in AD, accounts for the overall difference between AD and controls. It is possible that an increase in intraneuronal calbindin protects these cells from degeneration and that failure of such a neuroprotective mechanism is a significant contributory factor in the pathogenesis of AD.

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PubMed2001

Attentional control in Alzheimer's disease.

Attentional control of executive function declines during the early stages of Alzheimer's disease. Controversy exists as to whether this decline results from a single global deficit or whether attentional control can be fractionated, with some aspects being more vulnerable than others. We investigated three proposed domains of attention, namely (i) focal attention, based on simple and choice reaction times; (ii) the capacity to resist distraction in a visual search task; and (iii) the capacity to divide attention between two simultaneous tasks. For each domain, two levels of difficulty were used to study Alzheimer's disease patients, who were compared with elderly and young control subjects. The unitary attentional hypothesis predicted that the impacts of level of difficulty, age and disease would be qualitatively similar across the three attentional domains. In fact we observed different patterns for each domain. We obtained no differential impairment for patients in the focal attentional task, whereas patients were somewhat more susceptible than control subjects to the similarity of the distractor items in visual search. Finally, we observed marked impairment in the capacity of Alzheimer's disease patients to combine performance on two simultaneous tasks, in contrast to preserved dual-task performance in the normal elderly group. These results suggest a need to fractionate executive processes, and reinforce earlier evidence for a specific dual-task processing deficit in Alzheimer's disease.

Adult↗
PubMed2001

The pupillary light reflex in aging and Alzheimer's disease.

The pupillary light reflex is reported to be reduced in amplitude in Alzheimer's disease (AD). The purpose of this study was to determine whether this effect is measurable under conditions typical of clinical rather than laboratory settings. A head-mounted infra-red videopupillometer was used to measure the amplitude of pupillary constriction in 12 patients with probable AD, 12 healthy age-matched older adults and 12 young adults. The constriction to the onset of bright light relative to the resting amplitude was significantly reduced in AD compared with both control groups. This result is consistent with an acetylcholine-related deficit in AD and supports the findings of Prettyman et al. and Fotiou et al. The impairment is likely to be caused by degeneration in relays in the midbrain but cholinergic deficits in the peripheral parasympathetic pathway cannot be excluded. The variation in pupillary response between individuals may preclude its use for diagnostic purposes. However, if the changes in pupillary response in AD are related to change in neurotransmitter status, then the value of such a technique may be in its use in providing an objective, non-invasive monitor of physiological abnormality with which to follow disease progression and treatment efficacy.

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PubMed2000

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.

OBJECTIVE: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimer's disease. DESIGN: Randomised, double blind, parallel group, placebo controlled trial. SETTING: 86 outpatient clinics in Europe and Canada. PARTICIPANTS: 653 patients with mild to moderate Alzheimer's disease. INTERVENTION: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. MAIN OUTCOME MEASURES: Scores on the 11 item cognitive subscale of the Alzheimer's disease assessment scale, the clinician's interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. RESULTS: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer's disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician's interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study. CONCLUSION: Galantamine is effective and well tolerated in Alzheimer's disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

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PubMed2000

Activation of caspase-3 in permanent and transient brain ischaemia in man.

Animal studies have shown brain ischaemia to cause oxidative damage to DNA and activation of caspase-3, leading to apoptosis. These changes may be exacerbated by reperfusion. To assess caspase-3 activation after transient and permanent brain ischaemia in man, we examined brain tissue from patients who had experienced a cardiac arrest with resuscitation or an atherothrombotic brain infarct, and died 12 h to 9 days later. Sections were immunostained for activated caspase-3 or the 89 kDa caspase-3-mediated cleavage product of poly(ADP-ribose) polymerase. Brain ischaemia caused activation of caspase-3 in macrophages/microglia. Some neurons showed delayed activation of caspase-3 after cardiac arrest, but very few in atherothrombotic infarcts. In man, activation of caspase-3 plays little part in neuronal death in atherothrombotic infarcts but may contribute to delayed death of neurons after cardiac arrest.

Adult↗
PubMed2000

Chronic stress in caregivers of dementia patients is associated with reduced lymphocyte sensitivity to glucocorticoids.

Caring for the chronically ill is associated with chronic distress. In view of the adverse effects of distress on cellular immune function, such distress may have implications for health. Indeed, it has been proposed that the hypothalamic-pituitary-adrenal (HPA) axis is a potential psychobiological mediator of these effects. In this study, we observed that elderly caregivers experienced greater distress and increased salivary cortisol than non-caregivers. In addition, caregivers had blunted mitogen-induced lymphocyte proliferation, lower mitogen-induced IL-2 production, and reduced lymphocyte sensitivity to glucocorticoids. These results indicate that chronic distress is associated with impaired cell-mediated immunity which is, in turn, associated with elevated basal steroid levels and altered steroid immunoregulation at the level of the lymphocyte.

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PubMed2000

Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropsychological function.

BACKGROUND: Vitamin B12 assay is part of the routine investigation of dementia, although few studies have investigated the effects of treatment on cognition. We examined the effects of B12 treatment on neuropsychological function and disease progression in patients presenting with dementia or cognitive impairment. METHODS: From 1432 patients who were assessed at the Bristol Memory Disorders Clinic, 125 patients with low serum B12 were identified. Sixty-six patients presenting with dementia, and 22 with cognitive impairment were seen for a second assessment after treatment. Changes in neuropsychological test scores were compared with those of patients with normal serum B12, matched by age and diagnosis. RESULTS: The majority of patients with low serum B12 had normal Hb and MCV values. We found no cases of reversible B12 deficiency dementia. The B12 treatment patients who presented with dementia showed no significant improvement, and no less deterioration, in their neuropsychological function than their matched group. However, a treatment effect was demonstrated among the patients presenting with cognitive impairment. These improved significantly compared to matched patients on the verbal fluency test (p<0.01). CONCLUSION: All patients with cognitive impairment should be investigated for B12 deficiency. Vitamin B12 treatment may improve frontal lobe and language function in patients with cognitive impairment, but rarely reverses dementia.

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PubMed2000

The sensitivity to change over time of the Bristol Activities of Daily Living Scale in Alzheimer's disease.

Activities of daily living scales can be a useful tool in assessing change in people with dementia, either as the disease progresses or in response to treatment. However, little data exist as to the sensitivity to change of instruments used. The Bristol Activities of Daily Living Scale was developed with assistance from the carers of community dwelling people with dementia to be completed by such people and has been shown to have internal consistency as well as face and construct validity. This study aimed to analyse the sensitivity to change of the Bristol Activities of Daily Living Scale in people with Alzheimer's disease receiving anticholinesterase medication. Using the Clinician's Global Rating of Change as a gold standard for change, differences between Bristol Activities of Daily Living Scale scores before and after medication were compared with change in Mini-Mental State Examination, Alzheimer's Disease Assessment Scale - Cognitive and the Nurses Observation Scale for Geriatric Patients, in 61 older adults receiving anticholinesterase medication for Alzheimer's disease. Both the Bristol Activities of Daily Living Scale and the Nurses Observation Scale for Geriatric Patients are sensitive and specific in predicting improvement or stability as measured by the clinician's global rating of change. However, unlike the Nurses Observation Scale for Geriatric Patients, change over time in the Bristol Activities of Daily Living Scale significantly correlates with change in the Mini-Mental State Examination and the Alzheimer's Disease Assessment Scale - Cognitive. The Bristol Activities of Daily Living Scale is sensitive to change in activities of daily living and shows the expected and desirable relationship with measures of cognition.

Activities of Daily Living↗