J A Nicoll

Newcastle University, Newcastle upon Tyne, ENG, United Kingdom

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Publications (159)856.37 Total impact

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    ABSTRACT: Objective: Traumatic brain injury (TBI) is a multi-factorial pathology with great inter-individual variability in response to injury and outcome. Mitochondria contain their own DNA (mtDNA) with genomic variants that have different physiological and pathological characteristics, including susceptibility to neurodegeneration. Given the central role of mitochondria in the pathophysiology of neurological injury, we hypothesized that its genomic variants may account for the variability in outcome following TBI. Methods: We undertook an analysis of mitochondrial haplogroups in a large, well-characterised cohort of 1094 TBI patients. A proportional odds model including age, brain CT characteristics, injury severity, pupillary reactivity, mitochondrial haplogroups and APOE was applied to Glasgow Outcome Score (GOS) data. Results: MtDNA had a significant association with 6-month GOS (p=0·008). Haplogroup K was significantly associated with favourable outcome (OR 1·64, CI 1·08-2·51; p=0·02). There was also a significant interaction between mitochondrial genome and age (p=0·002), with a strong protective effect of both haplogroups T (p=0·015) and K (p=0·017) with advancing age. We also found a strong interaction between APOE and mitochondrial haplogroups (p=0·001), indicating a protective effect of haplogroup K in carriers of the APOE ε4 allele. Interpretation: These findings reveal an interplay between mitochondrial DNA, pathophysiology of TBI and ageing. Haplogroups K and T, which share a common maternal ancestor, are shown as protective in TBI. The data also suggest that the APOE pathways interact with genetically-regulated mitochondrial functions in the response to acute injury, as previously reported in Alzheimer's disease. ANN NEUROL 2014. © 2014 American Neurological Association.
    Annals of Neurology 02/2014; · 11.19 Impact Factor
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    ABSTRACT: Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-β immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-β42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcγ receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-β and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-β42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-β42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-β immunization, the microglial functional state is altered in association with reduced amyloid-β and tau pathology. The results suggest that, in the long term, amyloid-β immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.
    Brain 08/2013; · 9.92 Impact Factor
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    ABSTRACT: Clinical outcome after traumatic brain injury (TBI) is variable and cannot easily be predicted. There is increasing evidence to suggest there may be genetic influences on outcome. Cytokines play an important role in mediating the inflammatory response provoked within the central nervous system after TBI. This study was designed to identify associations between cytokine gene polymorphisms and clinical outcome 6-months after head injury. A prospectively identified cohort of patients (n=1096, age range 0-93, mean age 37) was utilised. Clinical outcome at 6 months was assessed using the Glasgow Outcome Scale. In an initial screen of 11 cytokine gene single nucleotide polymorphisms (SNPs) previously associated with disease susceptibility or outcome (TNFA -238 and -308, IL6 -174, -572 and -597, IL1A -889, IL1B -31, -511 and +3953 and TGFB -509 and -800) TNFA -308 was identified as having a likely association. The TNFA -308 SNP was further evaluated and a significant association was identified, with 39% of allele 2 carriers having an unfavourable outcome compared with 31% of non-carriers (adjusted OR 1.67, CI 1.19-2.35, p=0.003). These findings are consistent with experimental and clinical data suggesting that neuroinflammation has an impact on clinical outcome after TBI and that TNFα plays an important role in this process.
    Journal of neurotrauma 06/2013; · 4.25 Impact Factor
  • D Boche, J A R Nicoll
    Neuropathology and Applied Neurobiology 02/2013; 39(1):1-2. · 4.84 Impact Factor
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    ABSTRACT: Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Aβ) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Aβ and then demonstrate the effects of this intervention on soluble Aβ, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Aβ, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Aβ. Since, soluble Aβ, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Aβ may not be effective unless it is performed very early in the disease process or combined with other therapies.
    PLoS ONE 01/2013; 8(9):e73631. · 3.73 Impact Factor
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    ABSTRACT: AIMS: Traumatic brain injury is a significant cause of morbidity and mortality worldwide. An epidemiological association between head injury and long-term cognitive decline has been described for many years and recent clinical studies have highlighted functional impairment within 12 months of a mild head injury. In addition chronic traumatic encephalopathy is a recently described condition in cases of repetitive head injury. There are shared mechanisms between traumatic brain injury and Alzheimer's disease, and it has been hypothesised that neuroinflammation, in the form of microglial activation, may be a mechanism underlying chronic neurodegenerative processes after traumatic brain injury. METHODS: This study assessed the microglial reaction after head injury in a range of ages and survival periods, from <24 hours survival through to 47 years survival. Immunohistochemistry for reactive microglia (CD68 and CR3/43) was performed on human autopsy brain tissue and assessed "blind" by quantitative image analysis. Head injury cases were compared to age matched controls, and within the traumatic brain injury group cases with diffuse traumatic axonal injury were compared to cases without diffuse traumatic axonal injury. RESULTS: A major finding was a neuroinflammatory response which develops within the first week and persists for several months after TBI, but has returned to control levels after several years. In cases with diffuse traumatic axonal injury the microglial reaction is particularly pronounced in the white matter. CONCLUSIONS: These results demonstrate that prolonged microglial activation is a feature of traumatic brain injury, but that the neuroinflammatory response returns to control levels after several years.
    Neuropathology and Applied Neurobiology 12/2012; · 4.84 Impact Factor
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    ABSTRACT: Aim:  Microglia form a high proportion of cells in glial tumours but their role in supporting or inhibiting tumour growth is unclear. Here we describe the establishment of an in vitro model to investigate their role in astrocytomas. Methods:  Rat hippocampal slices were prepared and, after 7 days to allow microglia to become quiescent, rat C6 astrocytic tumour cells were added. Over the following 7 days, infiltration and cell death were studied using fluorescent C6 tumour cells and confocal microscopy; immunophenotyping of microglia was performed using CD68 (phagocytosis), MHCII (antigen-presentation) and Iba1 (microglial marker regardless of functional state). Cell proliferation was assessed using Ki67 and qPCR to detect cytokine expression. Sham and control groups were included. Results:  Microscopy showed proliferation of C6 tumour cells with both infiltration of tumour cells into the hippocampal tissue and of microglia amongst the tumour cells. Confocal experiments confirmed increasing tumour cell infiltration into the hippocampal slice with time (P<0.001), associated with cell death (σ=0.313, P=0.022). Ki67 showed increased proliferation (P<0.001), of both tumour cells and Iba1+ microglia and increased microglial phagocytosis (CD68: P<0.001). Expression of proinflammatory cytokines IL1, IL6 and TNFα were downregulated with expression of the anti-inflammatory cytokine TGFβ1 maintained. Conclusion:  This model allows study of the proliferation and infiltration of astrocytic tumour cells in CNS tissue and their interaction with microglia. Our data suggest that microglial function is altered in the presence of tumour cells, putatively facilitating tumour progression. Manipulation of the microglial functional state may have therapeutic value for astrocytic tumours. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society.
    Neuropathology and Applied Neurobiology 05/2012; · 4.84 Impact Factor
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    ABSTRACT: Failure of elimination of amyloid-β (Aβ) from the brain and vasculature appears to be a key factor in the etiology of sporadic Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). In addition to age, possession of an apolipoprotein E (APOE) ε4 allele is a strong risk factor for the development of sporadic AD. The present study tested the hypothesis that possession of the APOE ε4 allele is associated with disruption of perivascular drainage of Aβ from the brain and with changes in cerebrovascular basement membrane protein levels. Targeted replacement (TR) mice expressing the human APOE3 (TRE3) or APOE4 (TRE4) genes and wildtype mice received intracerebral injections of human Aβ(40). Aβ(40) aggregated in peri-arterial drainage pathways in TRE4 mice, but not in TRE3 or wildtype mice. The number of Aβ deposits was significantly higher in the hippocampi of TRE4 mice than in the TRE3 mice, at both 3- and 16-months of age, suggesting that clearance of Aβ was disrupted in the brains of TRE4 mice. Immunocytochemical and Western blot analysis of vascular basement membrane proteins demonstrated significantly raised levels of collagen IV in 3-month-old TRE4 mice compared with TRE3 and wild type mice. In 16-month-old mice, collagen IV and laminin levels were unchanged between wild type and TRE3 mice, but were lower in TRE4 mice. The results of this study suggest that APOE4 may increase the risk for AD through disruption and impedance of perivascular drainage of soluble Aβ from the brain. This effect may be mediated, in part, by changes in age-related expression of basement membrane proteins in the cerebral vasculature.
    PLoS ONE 01/2012; 7(7):e41636. · 3.73 Impact Factor
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    ABSTRACT: The brain is the only organ in which there is a significant problem with elimination of amyloid β with age, and substantial accumulation of amyloid β in Alzheimer's disease. Here we examine the pathways by which amyloid β is eliminated from the brain and the reasons why elimination fails with age. Lymphatic drainage of interstitial fluid and solutes, such as amyloid β, appears to be along the basement membranes of cerebral capillaries and arteries to cervical lymph nodes. Enzymes, such as neprilysin, that degrade amyloid β, and mechanisms for absorption of amyloid β into the blood are distributed along the lymphatic drainage pathways but they fail with age. As arteries themselves age, transport of amyloid β along perivascular drainage pathways also fails and results in cerebral amyloid angiopathy. We review the results of immunotherapy designed to clear amyloid β from the brain, and we suggest that a clear understanding of how amyloid β is eliminated may result in more effective therapies for Alzheimer's disease.
    09/2011: pages 97 - 101; , ISBN: 9781444341256
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    ABSTRACT: Unverricht-Lundborg disease (EPM1A), also known as Baltic myoclonus, is the most common form of progressive myoclonic epilepsy. It is inherited as an autosomal recessive trait, due to mutations in the Cystatin-B gene promoter region. Although there is much work on rodent models of this disease, there is very little published neuropathology in patients with EPM1A. Here, we present the neuropathology of a patient with genetically confirmed EPM1A, who died at the age of 76. There was atrophy and gliosis affecting predominantly the cerebellum, frontotemporal cortex, hippocampus and thalamus. We have identified neuronal cytoplasmic inclusions containing the lysosomal proteins, Cathepsin-B and CD68. These inclusions also showed immunopositivity to both TDP-43 and FUS, in some cases associated with an absence of normal neuronal nuclear TDP-43 staining. There were also occasional ubiquitinylated neuronal intranuclear inclusions, some of which were FUS immunopositive. This finding is consistent with neurodegeneration in EPM1A as at least a partial consequence of lysosomal damage to neurons, which have reduced Cystatin-B-related neuroprotection. It also reveals a genetically defined neurodegenerative disease with both FUS and TDP-43 related pathology.
    Acta Neuropathologica 03/2011; 121(3):421-7. · 9.73 Impact Factor
  • Nathan C. Denham, James A. R. Nicoll, Delphine Boche
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    ABSTRACT: Alzheimer’s disease (AD) was first described more than 100 years ago; however, the mechanisms underlying its pathogenesis are still poorly understood. Current theories suggest a pivotal role for the protein amyloid-β (Aβ) and many of the novel treatments for AD focus on Aβ. In this chapter, we discuss evidence that Aβ underpins the cognitive decline as a result of direct and indirect toxicity of the peptide on synapses in the cerebral cortex and hippocampus. Furthermore, we will follow the promise that Aβ immunisation holds to alter the natural history of AD, from its beginnings in animal models to the current research on humans. The success seen in mice in preventing both synapse loss and reducing functional decline is yet to be matched in humans and serious adverse events in patients stopped the initial vaccination approach. Research, however, is continuing in human AD aiming to provide a greater understanding of the mechanisms underlying the immune response and the potential effects of immunisation on preventing or reversing cognitive impairment.
    12/2010: pages 269-287;
  • A I Ahmed, C A Eynon, L Kinton, J A R Nicoll, A Belli
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    ABSTRACT: Acute disseminated encephalomyelitis (ADEM) is a rare, acute demyelinating condition. Although it usually presents in an acute or subacute manner over days, its clinical course may be rapid with symptoms and signs of severe intracerebral mass effect secondary to cerebral oedema. Case report and literature review. We report a case of a patient presenting with a hyperacute course manifested by rapid loss of consciousness and focal neurological signs. Management with emergency hemicraniectomy and steroids resulted in rapid neurological improvement and minimal long-term deficit. We believe that only surgical decompression is likely to be life saving in similar cases of hyperacute cerebral oedema due to ADEM. The wide decompression performed was concordant with that indicated for traumatic brain swelling. Such aggressive management is vindicated by the rapid recovery shown by our patient within days of surgery and the finding of minimal neurological sequelae at 3 months.
    Neurocritical Care 12/2010; 13(3):393-5. · 3.04 Impact Factor
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    ABSTRACT: In Alzheimer's disease (AD), microglial activation prompted by the presence of amyloid has been proposed as an important contributor to the neurodegenerative process. Conversely following Aβ immunization, phagocytic microglia have been implicated in plaque removal, potentially a beneficial effect. We have investigated the effects of Aβ42 immunization on microglial activation and the relationship with Aβ42 load in human AD. Immunostaining against Aβ42 and microglia (CD68 and HLA-DR) was performed in nine immunized AD cases (iAD - AN1792, Elan Pharmaceuticals) and eight unimmunized AD (cAD) cases. Although the Aβ42 load (% area stained of total area examined) was lower in the iAD than the cAD cases (P=0.036), the CD68 load was higher (P=0.046). In addition, in the iAD group, the CD68 level correlated with the Aβ42 load, consistent with the immunization upregulating microglial phagocytosis when plaques are present. However, in two long-surviving iAD patients in whom plaques had been extensively cleared, the CD68 load was less than in controls. HLA-DR quantification did not show significant difference implying that the microglial activation may have related specifically to their phagocytic function. CD68 and HLA-DR loads in the pons were similar in both groups, suggesting that the differences in microglial activation in the cortex were due to the presence of AD pathology. Our findings suggest that Aβ42 immunization modifies the function of microglia by increasing their phagocytic activity and when plaques have been cleared, the level of phagocytosis is decreased below that seen in unimmunized AD.
    Neuropathology and Applied Neurobiology 12/2010; 37(5):513-24. · 4.84 Impact Factor
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    ABSTRACT: The amyloid cascade hypothesis of Alzheimer's disease (AD) is testable: it implies that interference with Abeta aggregation and plaque formation may be therapeutically useful. Abeta42 immunisation of amyloid precursor protein (APP) transgenic mice prevented plaque formation and caused removal of existing plaques. The first clinical studies of Abeta immunisation in AD patients (AN1792, Elan Pharmaceuticals) were halted when some patients suffered side effects. Since our confirmation that Abeta immunisation can prompt plaque removal in human AD, we have performed a clinical and neuropathological follow up of AD patients in the initial Elan Abeta immunisation trial. In immunised AD patients, we found: a lower Abeta load, with evidence that plaques had been removed; a reduced tau load in neuronal processes, but not in cell bodies; and no evidence of a beneficial effect on synapses. There were pathological "side effects" including: increased microglial activation; increased cerebral amyloid angiopathy; and there is some evidence for increased soluble/oligomeric Abeta. A pathophysiological mechanism involving effects on the cerebral vasculature is proposed for the clinical side effects observed with some active and passive vaccine protocols. Our current knowledge of the effects of Abeta immunotherapy is based on functional information from the early clinical trials and a few post mortem cases. Several further clinical studies are underway using a variety of protocols and important clinical, imaging and neuropathological data will become available in the near future. The information obtained will be important in helping to understand the pathogenesis not only of AD but also of other neurodegenerative disorders associated with protein aggregation.
    Acta Neuropathologica 09/2010; 120(3):369-84. · 9.73 Impact Factor
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    ABSTRACT: Apolipoprotein E (APOE) genotype is the major genetic risk factor for sporadic Alzheimer's disease (AD) but it is unclear how this is mediated. Most studies of APOE genotype have used case-control design to compare groups differing by two variables: i.e. dementia and AD pathology, so it is unclear to which of these variables APOE genotype is more strongly related. The prospective Medical Research Council Cognitive Function and Ageing Study neuropathology cohort is population-based sample in which donations are unbiased by dementia status. We investigated the association between APOE genotypes and neuropathological and cognitive data in this cohort (n = 310). APOEε4 was associated with an increased risk of diffuse plaques, neuritic plaques, tangles and cerebral amyloid angiopathy. APOEε4 was not associated with infarcts, lacunes, haemorrhages or small vessel disease. APOEε2 appeared to have a protective effect on AD pathology and also on the risk of cortical atrophy. APOE genotype had a non-significant effect on the presence of dementia after adjusting for AD pathology. APOE genotype is associated with each of the key features of AD pathology but not with cerebrovascular disease other than cerebral amyloid angiopathy. The excess risk of dementia in those with an APOEε4 allele is explained by the pathological features of AD. However, it remains unclear to what extent cognitive dysfunction is caused by these specific pathological features or more directly by closely related APOE-associated mechanisms.
    Neuropathology and Applied Neurobiology 09/2010; 37(3):285-94. · 4.84 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) pathology is characterised by aggregation in the brain of amyloid-beta (Abeta) peptide and hyperphosphorylated tau (phospho-tau), although how these proteins interact in disease pathogenesis is unclear. Abeta immunisation results in removal of Abeta from the brain but cognitive decline continues to progress, possibly due to persistent phospho-tau. We quantified phospho-tau and Abeta42 in the brains of 10 AD patients (iAD) who were actively immunised with Abeta42 (AN1792, Elan Pharmaceuticals) compared with 28 unimmunised AD cases (cAD). The phospho-tau load was lower in the iAD than the cAD group in the cerebral cortex (cAD 1.08% vs. iAD 0.72%, P = 0.048), CA1 hippocampus (cAD 2.26% vs. iAD 1.05%; P = 0.001), subiculum (cAD 1.60% vs. iAD 0.31%; P = 0.001) and entorhinal cortex (cAD 1.10% vs. iAD 0.18%; P < 0.001). Assessment of the localisation within neurons of phospho-tau indicated that the Abeta immunotherapy-associated reduction was confined to neuronal processes, i.e. neuropil threads and dystrophic neurites. However, the phospho-tau accumulation in the neuronal cell bodies, contributing to neurofibrillary tangles, appeared not to be affected. In showing that Abeta immunisation can influence phospho-tau pathology, we confirm the position of Abeta as a target for modifying tau accumulation in AD and demonstrate a link between these proteins. However, the continuing progression of cognitive decline in AD patients after Abeta immunisation may be explained by its lack of apparent effect on tangles.
    Acta Neuropathologica 07/2010; 120(1):13-20. · 9.73 Impact Factor
  • Delphine Boche, James A R Nicoll
    Brain 05/2010; 133(Pt 5):1297-9. · 9.92 Impact Factor
  • V Hugh Perry, James A R Nicoll, Clive Holmes
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    ABSTRACT: Microglia, the resident macrophages of the CNS, are exquisitely sensitive to brain injury and disease, altering their morphology and phenotype to adopt a so-called activated state in response to pathophysiological brain insults. Morphologically activated microglia, like other tissue macrophages, exist as many different phenotypes, depending on the nature of the tissue injury. Microglial responsiveness to injury suggests that these cells have the potential to act as diagnostic markers of disease onset or progression, and could contribute to the outcome of neurodegenerative diseases. The persistence of activated microglia long after acute injury and in chronic disease suggests that these cells have an innate immune memory of tissue injury and degeneration. Microglial phenotype is also modified by systemic infection or inflammation. Evidence from some preclinical models shows that systemic manipulations can ameliorate disease progression, although data from other models indicates that systemic inflammation exacerbates disease progression. Systemic inflammation is associated with a decline in function in patients with chronic neurodegenerative disease, both acutely and in the long term. The fact that diseases with a chronic systemic inflammatory component are risk factors for Alzheimer disease implies that crosstalk occurs between systemic inflammation and microglia in the CNS.
    Nature Reviews Neurology 03/2010; 6(4):193-201. · 15.52 Impact Factor
  • Alzheimers & Dementia - ALZHEIMERS DEMENT. 01/2010; 6(4).
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    ABSTRACT: The cellular pathology of astrocytes in brain ageing and their role in modulating the brain's response to neurodegenerative pathology remain incompletely understood. Using quantitative ELISA, we have investigated glial fibrillary acidic protein (GFAP) expression in the population-based neuropathology cohort of the Medical Research Council Cognitive Function and Ageing Study to determine: (1) the population variation in the astroglial hypertrophic response, (2) its relationship to the presence of Alzheimer-type pathology, and (3) its association with cognition. Increasing GFAP was found with increasing Braak stage, levels increasing even at early stages. Within Braak stages, GFAP did not differ between demented and non-demented individuals, but there was greater variance in GFAP in the demented. Possession of ApoE epsilon4 was associated with slightly increased GFAP levels (not significant) for given amyloid beta protein loads. In a population-based sample, increasing gliosis precedes development of Alzheimer lesions. Population variation in GFAP with varying Alzheimer lesion burdens suggests that they are not the only driver for astrogliosis. GFAP was not independently predictive of dementia, but the variation in astrocytic responses may be a factor modulating brain responses to neurodegenerative pathology.
    Dementia and Geriatric Cognitive Disorders 06/2009; 27(5):465-73. · 2.79 Impact Factor

Publication Stats

7k Citations
856.37 Total Impact Points

Institutions

  • 2013
    • Newcastle University
      • Institute for Ageing and Health
      Newcastle upon Tyne, ENG, United Kingdom
  • 2008–2013
    • University Hospital Southampton NHS Foundation Trust
      Southampton, England, United Kingdom
  • 2004–2012
    • The University of Edinburgh
      • • Division of Pathology
      • • Division of Psychiatry
      Edinburgh, Scotland, United Kingdom
  • 2002–2011
    • University of Southampton
      • Clinical Neurosciences
      Southampton, ENG, United Kingdom
    • Imperial College London
      • Faculty of Medicine
      Londinium, England, United Kingdom
  • 1996–2006
    • University of Glasgow
      • Division of Anatomy
      Glasgow, Scotland, United Kingdom
  • 2003
    • King's College London
      • Department of Clinical Neuroscience
      London, ENG, United Kingdom
  • 1992
    • University of Bristol
      Bristol, England, United Kingdom
  • 1991–1992
    • Bristol Hospital
      Bristol, Connecticut, United States