Matthew R. Garnett

Bio: Matthew R. Garnett is an academic researcher from University of Cambridge. The author has contributed to research in topics: Intracranial pressure & Normal pressure hydrocephalus. The author has an hindex of 11, co-authored 41 publications receiving 394 citations. Previous affiliations of Matthew R. Garnett include Necker-Enfants Malades Hospital.

Injuries to Inferior Vermis and Dentate Nuclei Predict Poor Neurological and Neuropsychological Outcome in Children With Malignant Posterior Fossa Tumors

Abstract: BACKGROUND: Children treated for a malignant posterior fossa tumor (PFT) are at risk of intellectual impairment. Its severity is not explained by age and radiotherapy alone. The current study was designed to define the correlations between the anatomical damage and the neurological/neuropsychological deficits in children with a malignant PFT. METHODS: Sixty-one consecutive children (mean age, 6.0 years) treated for a malignant PFT with surgery, chemotherapy, and radiotherapy underwent a detailed neuropsychological evaluation, including a full-scale intelligence quotient (FSIQ), on average 5.6 years after the diagnosis. The neurological examination was recorded 1 month after surgery and at the time of the neuropsychological evaluation. Cerebellar and brain injuries were scored based on the magnetic resonance imaging (MRI). Correlation of these injuries with neurological and cognitive outcome were performed after adjustment for other potential risk factors (radiotherapy schedule, age, hydrocephalus, duration of symptoms, socioeconomic status, and surgical complications). RESULTS: Neurological deficits were strong predictors of low cognitive performances irrespective of the other risk factors. The extent of cerebellar deficits and fine motor dexterity impairment were correlated with the degree of damage to the dentate nuclei and inferior vermis. The IQ scores were inversely correlated with the severity of the damage to the dentate nuclei; mean FSIQ was 83 if they were both intact and 65 in the case of bilateral damage (P ¼ .009). CONCLUSIONS: Damage to the dentate nuclei and to the inferior vermis, observed on MRI, predict the degree of impairment of neurological and neuropsychological functions in children treated for a malignant PFT. Cancer 2009;115:1338–47. V C 2009 American Cancer Society.

A map of transcriptional heterogeneity and regulatory variation in human microglia.

Abstract: Microglia, the tissue-resident macrophages of the central nervous system (CNS), play critical roles in immune defense, development and homeostasis. However, isolating microglia from humans in large numbers is challenging. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single-cell and bulk RNA sequencing, we identify how age, sex and clinical pathology influence microglia gene expression and which genetic variants have microglia-specific functions using expression quantitative trait loci (eQTL) mapping. We follow up one of our findings using a human induced pluripotent stem cell-based macrophage model to fine-map a candidate causal variant for Alzheimer's disease at the BIN1 locus. Our study provides a population-scale transcriptional map of a critically important cell for human CNS development and disease.

A map of transcriptional heterogeneity and regulatory variation in human microglia

Abstract: Microglia, the tissue resident macrophages of the CNS, are implicated in a broad range of neurological pathologies, from acute brain injury to dementia. Here, we profiled gene expression variation in primary human microglia isolated from 141 patients undergoing neurosurgery. Using single cell and bulk RNA sequencing, we defined distinct cellular populations of acutely in vivo-activated microglia, and characterised a dramatic switch in microglial population composition in patients suffering from acute brain injury. We mapped expression quantitative trait loci (eQTLs) in human microglia and show that many disease-associated eQTLs in microglia replicate well in a human induced pluripotent stem cell (hIPSC) derived macrophage model system. Using ATAC-seq from 95 individuals in this hIPSC model we fine-map candidate causal variants at risk loci for Alzheimer9s disease, the most prevalent neurodegenerative condition in acute brain injury patients. Our study provides the first population-scale transcriptional map of a critically important cell for neurodegenerative disorders.

Continuous multimodality monitoring in children after traumatic brain injury-preliminary experience

Abstract: We gratefully acknowledge financial support as follows. Research support: the Medical Research Council (MRC, Grant Nos. G0600986 ID79068 and G1002277 ID98489) and the National Institute for Health Research Biomedical Research Centre (NIHR BRC) Cambridge (Neuroscience Theme; Brain Injury and Repair Theme). Authors’ support: Peter J Hutchinson – NIHR Research Professorship, Academy of Medical Sciences/Health Foundation Senior Surgical Scientist Fellowship and NIHR Cambridge BRC. Joseph Donnelly is supported by a Woolf Fisher Scholarship. MC- NIHR BRC.

Changes in elemental concentrations are associated with early stages of apoptosis in human monocyte-macrophages exposed to oxidized low-density lipoprotein: an X-ray microanalytical study.

Abstract: This study examines ion homeostasis in monocyte-macrophages committed to death by apoptosis. X-ray microanalysis has been used to demonstrate that intracellular concentrations of potassium decreased whilst those of sodium increased following 3 h of exposure to 100 microg/ml of oxidized low-density lipoprotein (LDL) in vitro. In contrast, the maximal incidence of cell death, as determined by the inability to exclude trypan blue, was not seen until 24 h of exposure. At 12 h, less than 1 per cent of cells were stained using terminal transferase-mediated DNA nick-end labelling, which is generally accepted as a marker of late stages in the apoptotic pathway. This is the first demonstration of early perturbations of ion homeostasis in monocyte-macrophages exposed to concentrations of oxidized LDL known to cause apoptosis.

A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer's disease.

Abstract: Late-onset Alzheimer's disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases. Currently, only a fraction of the genetic variants underlying Alzheimer's disease have been identified. Here we show that increased sample sizes allowed identification of seven previously unidentified genetic loci contributing to Alzheimer's disease. This study highlights microglia, immune cells and protein catabolism as relevant to late-onset Alzheimer's disease, while identifying and prioritizing previously unidentified genes of potential interest. We anticipate that these results can be included in larger meta-analyses of Alzheimer's disease to identify further genetic variants that contribute to Alzheimer's pathology.

Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes

Abstract: Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA and CASS4.