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1.  Association of Interleukin-1 Gene Polymorphisms with Alzheimer’s Disease 
Annals of neurology  2000;47(3):365-368.
Interleukin-1 (IL-1) is markedly overexpressed in Alzheimer’s disease. We found the IL-1A 2,2 genotype in 12.9% of 232 neuropathologically confirmed Alzheimer’s disease patients and 6.6% of 167 controls from four centers in the United Kingdom and United States (odds ratio, 3.0; controlled for age and for ApoE [apolipoprotein E] genotype). Homozygosity for both allele 2 of IL-1A and allele 2 of IL-1B conferred even greater risk (odds ratio, 10.8). IL-1 genotypes may confer risk for Alzheimer’s disease through IL-1 overexpression and IL-1– driven neurodegenerative cascades.
PMCID: PMC3833599  PMID: 10716257
2.  Sequestration and Microvascular Congestion Are Associated With Coma in Human Cerebral Malaria 
The Journal of Infectious Diseases  2011;205(4):663-671.
The pathogenesis of coma in severe Plasmodium falciparum malaria remains poorly understood. Obstruction of the brain microvasculature because of sequestration of parasitized red blood cells (pRBCs) represents one mechanism that could contribute to coma in cerebral malaria. Quantitative postmortem microscopy of brain sections from Vietnamese adults dying of malaria confirmed that sequestration in the cerebral microvasculature was significantly higher in patients with cerebral malaria (CM; n = 21) than in patients with non-CM (n = 23). Sequestration of pRBCs and CM was also significantly associated with increased microvascular congestion by infected and uninfected erythrocytes. Clinicopathological correlation showed that sequestration and congestion were significantly associated with deeper levels of premortem coma and shorter time to death. Microvascular congestion and sequestration were highly correlated as microscopic findings but were independent predictors of a clinical diagnosis of CM. Increased microvascular congestion accompanies coma in CM, associated with parasite sequestration in the cerebral microvasculature.
doi:10.1093/infdis/jir812
PMCID: PMC3266137  PMID: 22207648
3.  A combined post-mortem magnetic resonance imaging and quantitative histological study of multiple sclerosis pathology 
Brain  2012;135(10):2938-2951.
Multiple sclerosis is a chronic inflammatory neurological condition characterized by focal and diffuse neurodegeneration and demyelination throughout the central nervous system. Factors influencing the progression of pathology are poorly understood. One hypothesis is that anatomical connectivity influences the spread of neurodegeneration. This predicts that measures of neurodegeneration will correlate most strongly between interconnected structures. However, such patterns have been difficult to quantify through post-mortem neuropathology or in vivo scanning alone. In this study, we used the complementary approaches of whole brain post-mortem magnetic resonance imaging and quantitative histology to assess patterns of multiple sclerosis pathology. Two thalamo-cortical projection systems were considered based on their distinct neuroanatomy and their documented involvement in multiple sclerosis: lateral geniculate nucleus to primary visual cortex and mediodorsal nucleus of the thalamus to prefrontal cortex. Within the anatomically distinct thalamo-cortical projection systems, magnetic resonance imaging derived cortical thickness was correlated significantly with both a measure of myelination in the connected tract and a measure of connected thalamic nucleus cell density. Such correlations did not exist between these markers of neurodegeneration across different thalamo-cortical systems. Magnetic resonance imaging lesion analysis depicted clearly demarcated subcortical lesions impinging on the white matter tracts of interest; however, quantitation of the extent of lesion-tract overlap failed to demonstrate any appreciable association with the severity of markers of diffuse pathology within each thalamo-cortical projection system. Diffusion-weighted magnetic resonance imaging metrics in both white matter tracts were correlated significantly with a histologically derived measure of tract myelination. These data demonstrate for the first time the relevance of functional anatomical connectivity to the spread of multiple sclerosis pathology in a ‘tract-specific’ pattern. Furthermore, the persisting relationship between metrics from post-mortem diffusion-weighted magnetic resonance imaging and histological measures from fixed tissue further validates the potential of imaging for future neuropathological studies.
doi:10.1093/brain/aws242
PMCID: PMC3470716  PMID: 23065787
multiple sclerosis; post-mortem imaging; diffusion imaging; white matter tracts; neurodegeneration
4.  Cognitive reserve, cortical plasticity and resistance to Alzheimer's disease 
There are aspects of the ageing brain and cognition that remain poorly understood despite intensive efforts to understand how they are related. Cognitive reserve is the concept that has been developed to explain how it is that some elderly people with extensive neuropathology associated with dementia show little in the way of cognitive decline. Cognitive reserve is intimately related to cortical plasticity but this also, as it relates to ageing, remains poorly understood at the present time. Despite the shortcomings in understanding, we do have some knowledge on which to base efforts to minimise the likelihood of an elderly person developing dementia. For some risks the evidence is far from secure, but resistance to Alzheimer's disease (AD) appears from epidemiological studies to be contributed to by avoiding hypertension in middle life, obesity, depression, smoking and diabetes and head injury and by undertaking extended years of education, physical exercise, and social and intellectual pursuits in middle and late life. Nutritional factors may also promote healthy brain ageing. Resistance to AD is also contributed to by genetic factors, particularly apolipoprotein E2, but some combinations of other genetic polymorphisms as well. Although multiple factors and possible interventions may influence cognitive reserve and susceptibility to dementia, much more work is required on the mechanisms of action in order to determine which, if any, may improve the clinical and epidemiological picture. Understanding of how such factors operate may lead to new initiatives to keep the elderly population in the 21st century able to lead active and fulfilling lives.
doi:10.1186/alzrt105
PMCID: PMC3334540  PMID: 22380508
5.  IL-21 and IL-21 Receptor Expression in Lymphocytes and Neurons in Multiple Sclerosis Brain 
The American Journal of Pathology  2011;178(2):794-802.
IL-17–producing CD4+ T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL-21, IL-22, and IL-6 under Th-17–polarizing conditions (IL-6 and transforming growth factor-β). In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21+ infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4+ cells. In contrast, IL-21R was much more broadly distributed on CD4+, CD19+, and CD8+ lymphocytes but not major histocompatibility complex class-II+ macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons.
doi:10.1016/j.ajpath.2010.10.043
PMCID: PMC3032888  PMID: 21281812
6.  Concurrent multiple sclerosis and amyotrophic lateral sclerosis: where inflammation and neurodegeneration meet? 
The concurrence of multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) is exceedingly rare and the pathological features have not been examined extensively. Here we describe the key pathological features of a 40 year old man with pathologically confirmed concurrent MS and ALS.
This is the most pathologically illustrative case of coincident MS and ALS demonstrating inflammatory and neurodegenerative features characteristic of each disease, and is the first to exhibit the presence of TDP-43 inclusions in this clinical entity. The intricate relationship between neuroinflammation and neurodegeneration in these diseases is discussed.
doi:10.1186/1742-2094-9-20
PMCID: PMC3308920  PMID: 22269588
multiple sclerosis; amyotrophic lateral sclerosis; neuropathology; inflammation; neurodegeneration
7.  Diffusion imaging of whole, post-mortem human brains on a clinical MRI scanner 
Neuroimage  2011;57(1-4):167-181.
Diffusion imaging of post mortem brains has great potential both as a reference for brain specimens that undergo sectioning, and as a link between in vivo diffusion studies and “gold standard” histology/dissection. While there is a relatively mature literature on post mortem diffusion imaging of animals, human brains have proven more challenging due to their incompatibility with high-performance scanners. This study presents a method for post mortem diffusion imaging of whole, human brains using a clinical 3-Tesla scanner with a 3D segmented EPI spin-echo sequence. Results in eleven brains at 0.94 × 0.94 × 0.94 mm resolution are presented, and in a single brain at 0.73 × 0.73 × 0.73 mm resolution. Region-of-interest analysis of diffusion tensor parameters indicate that these properties are altered compared to in vivo (reduced diffusivity and anisotropy), with significant dependence on post mortem interval (time from death to fixation). Despite these alterations, diffusion tractography of several major tracts is successfully demonstrated at both resolutions. We also report novel findings of cortical anisotropy and partial volume effects.
Research highlights
► Acquisition and processing protocols for diffusion MRI of post-mortem human brains. ► Effect of post-mortem and scan intervals on diffusion indices. ► Tractography in post-mortem human brains. ► Radial diffusion anisotropy in cortical gray matter.
doi:10.1016/j.neuroimage.2011.03.070
PMCID: PMC3115068  PMID: 21473920
Diffusion tensor imaging; Tractography; Post mortem; Human; Brain
8.  Pro: Can neuropathology really confirm the exact diagnosis? 
Recent advances in the clinical diagnostic instruments for diagnosing Alzheimer's disease (AD) and in neuroimaging may cast doubt in the minds of some practitioners about the continued need for neuropathology to provide the ultimate diagnosis. Certainly the majority of cases of AD can be clinically correctly diagnosed by experienced clinicians but many cases are given this label by less experienced practitioners. Even after the most thorough work-up, a few cases of confidently diagnosed AD turn out to be something else when microscopy of the brain is undertaken. Even for neuropathologists, however, it can be difficult to correctly assign cognitive decline to the various pathological processes that can be found together in an older brain. We need further clinicopathogical study to enlighten us about, for example, the contribution of commonly found cerebrovascular disease to dementia. Human studies are also needed to explore the changes in pathology that new treatments for AD may produce.
doi:10.1186/alzrt33
PMCID: PMC2876787  PMID: 20497619
9.  Focal and Diffuse Cortical Degenerative Changes in a Marmoset Model of Multiple Sclerosis 
Background
Degenerative features such as neuronal, glial, synaptic and axonal loss have been identified in neocortical and other grey matter structures in patients with multiple sclerosis, but mechanisms for neurodegeneration are unclear. Cortical demyelinating lesions are a potential cause of this degeneration but the pathological and clinical significance of these lesions is uncertain, as they remain difficult to identify and study in vivo. In this study we aimed to describe and quantify cellular and subcellular pathology in the cortex of MOG-induced marmoset experimental autoimmune encephalomyelitis using quantitative immunohistochemical methods.
Results
We found evidence of diffuse axonal damage occurring throughout cortical grey matter with evidence for synaptic loss and gliosis and a 13.6% decrease in neuronal size and occurring in deep cortical layers. Evidence of additional axonal damage and a 29.6–36.5% loss of oligodendrocytes was found in demyelinated cortical lesions. Leucocortical lesions also showed neuronal loss of 22.2% and a 15.8% increase in oligodendrocyte size.
Conclusions
The marmoset EAE model therefore shows both focal and generalised neurodegeneration. The generalised changes cannot be directly related to focal lesions, suggesting that they either are a consequence of diffusible inflammatory factors or secondary to remote lesions acting through trans-synaptic or retrograde degeneration.
doi:10.1177/1352458509360362
PMCID: PMC2874633  PMID: 20194580
multiple sclerosis; cortex; inflammation; neurodegeneration; experimental autoimmune encephalomyelitis; marmoset; Callithrix jacchus; immunohistochemistry; demyelination; myelin oligodendrocyte glycoprotein
10.  IL-21 and IL-21 Receptor Expression in Lymphocytes and Neurons in Multiple Sclerosis Brain 
The American Journal of Pathology  2011;178(2):794-802.
IL-17–producing CD4+ T cells (Th-17) contribute to the pathogenesis of experimental autoimmune encephalomyelitis and are associated with active disease in multiple sclerosis (MS). In addition to IL-17, Th-17 cells can also express IL-21, IL-22, and IL-6 under Th-17–polarizing conditions (IL-6 and transforming growth factor-β). In this study we investigated IL-21 and IL-21 receptor (IL-21R) expression in MS lesions by in situ hybridization and immunohistochemistry. We detected strongly IL-21+ infiltrating cells predominantly in acute but also in chronic active white matter MS lesions in which IL-21 expression was restricted to CD4+ cells. In contrast, IL-21R was much more broadly distributed on CD4+, CD19+, and CD8+ lymphocytes but not major histocompatibility complex class-II+ macrophages/microglia. Interestingly, in cortical areas we detected both IL-21 and IL-21R expression by neurons. These findings suggest role(s) for IL-21 in both the acute and chronic stages of MS via direct effects on T and B lymphocytes and, demonstrated for the first time, also on neurons.
doi:10.1016/j.ajpath.2010.10.043
PMCID: PMC3032888  PMID: 21281812
11.  Diffuse Cortical Atrophy in a Marmoset Model of Multiple Sclerosis 
Neuroscience letters  2008;437(2):121-124.
Aims
Marmoset experimental autoimmune encephalomyelitis (EAE) has previously been shown to replicate the essential features of both white matter and grey matter lesions of MS. This study set out to investigate whether cortical atrophy occurs in marmoset EAE and whether cortical thinning is related to the presence of focal, demyelinated cortical lesions.
Methods
17 leucocortical lesions and 13 subpial lesions were identified in 6 EAE cases. Cortical thickness surrounding these lesions was recorded and compared with matched cortical areas from 5 control animals.
Results
We found a diffuse13–21% loss of cortical thickness in all areas of EAE cortex compared with control animals but there was no additional loss seen in demyelinated verses myelinated EAE cortex. These findings could not be accounted for by effects of age, sex and disease duration.
Conclusions
These findings confirm the presence of significant cortical atrophy in this model. We conclude that localised cortical demyelination is not responsible for the major part of the atrophy observed and that cortical thinning is largely due to more diffuse or more remote factors. Marmoset EAE is an invaluable tool which can be used to further investigate the cause and the substrate of cortical loss in demyelinating diseases.
doi:10.1016/j.neulet.2008.03.069
PMCID: PMC2391306  PMID: 18440142
multiple sclerosis; experimental autoimmune encephalomyelitis; marmoset; callithrix jacchus; cortical atrophy; cortical lesions
12.  Immunohistochemical study of N-epsilon-carboxymethyl lysine (CML) in human brain: relation to vascular dementia 
BMC Neurology  2007;7:35.
Background
Advanced glycation end-products (AGEs) and their receptor (RAGE) occur in dementia of the Alzheimer's type and diabetic microvascular disease. Accumulation of AGEs relates to risk factors for vascular dementia with ageing, including hypertension and diabetes. Cognitive dysfunction in vascular dementia may relate to microvascular disease resembling that in diabetes. We tested if, among people with cerebrovascular disease, (1) those with dementia have higher levels of neuronal and vascular AGEs and (2) if cognitive dysfunction depends on neuronal and/or vascular AGE levels.
Methods
Brain Sections from 25 cases of the OPTIMA (Oxford Project to Investigate Memory and Ageing) cohort, with varying degrees of cerebrovascular pathology and cognitive dysfunction (but only minimal Alzheimer type pathology) were immunostained for Nε-(carboxymethyl)-lysine (CML), the most abundant AGE. The level of staining in vessels and neurons in the cortex, white matter and basal ganglia was compared to neuropsychological and other clinical measures.
Results
The probability of cortical neurons staining positive for CML was higher in cases with worse cognition (p = 0.01) or a history of hypertension (p = 0.028). Additionally, vascular CML staining related to cognitive impairment (p = 0.02) and a history of diabetes (p = 0.007). Neuronal CML staining in the basal ganglia related to a history of hypertension (p = 0.002).
Conclusion
CML staining in cortical neurons and cerebral vessels is related to the severity of cognitive impairment in people with cerebrovascular disease and only minimal Alzheimer pathology. These findings support the possibility that cerebral accumulation of AGEs may contribute to dementia in people with cerebrovascular disease.
doi:10.1186/1471-2377-7-35
PMCID: PMC2100062  PMID: 17939855
13.  Dysfunction of the mTOR pathway is a risk factor for Alzheimer’s disease 
Background
The development of disease-modifying therapies for Alzheimer’s disease is hampered by our lack of understanding of the early pathogenic mechanisms and the lack of early biomarkers and risk factors.
We have documented the expression pattern of mTOR regulated genes in the frontal cortex of Alzheimer’s disease patients. We have also examined the functional integrity of mTOR signaling in peripheral lymphocytes in Alzheimer’s disease patients relative to healthy controls.
Results
In the brain mTOR is seen to control molecular functions related to cell cycle regulation, cell death and several metabolic pathways. These downstream elements of the mTOR signaling cascade are deregulated in the brain of Alzheimer’s disease patients well before the development of pathology. This dysregulation of the mTOR downstream signaling cascade is not restricted to the brain but appears to be systemic and can be detected in peripheral lymphocytes as a reduced Rapamycin response.
Conclusions
The dysfunction of the signaling pathways downstream of mTOR may represent a risk factor for Alzheimer’s disease and is independent of the ApoE status of the patients.
We have also identified the molecular substrates of the beneficial effects of Rapamycin on the nervous system. We believe that these results can further inform the development of clinical predictive tests for the risk of Alzheimer’s disease in patients with mild cognitive impairment.
doi:10.1186/2051-5960-1-3
PMCID: PMC3776211  PMID: 24252508
mTOR; cell cycle; Alzheimer’s disease; risk factor; ApoE

Results 1-13 (13)