Sir Hugh Cairns: a pioneering collaborator.

In April 1988, Peter Schurr delivered the twelfth Sir Hugh Cairns Memorial Lecture to the Society of British Neurological Surgeons. In his lecture, The Cairns Tradition, Schurr extolled the personal virtues of Cairns. He encouraged his colleagues to draw inspiration from Cairns' renowned determination, organisation, drive for perfection, compassion, and commitment to the training of those around him. Indeed, Cairns' own personality has come to define the specialty which he established in Britain. Today's neurosurgeons are, whether knowingly or not, formed in his image. But there is a side to Hugh Cairns that has been lost in the telling of his remarkable story, and yet it played a central role in his greatest achievements. This is the side of himself which he turned towards others. Throughout his career, Cairns received an inordinate number of personal accolades. His tutelage under Cushing during a formative trip to America and the impact of his role in caring for T. E. Lawrence are well known to many. But, more than thirty years after Peter Schurr's memorial lecture, and following the eightieth anniversary of the department of neurosurgery founded by Cairns in Oxford, it is his work as a pioneering collaborator which defines his legacy today, and which calls us to learn yet another lesson from his remarkable life. In this legacy article, we review the origins of Cairns' collaborative spirit and uncover the achievements he shared with Charles Hallpike, Howard Florey, Derek Denny-Brown, William Ritchie Russell, Ludwig Guttman, and Peter Medawar, among many others.

Rare variants in the CYP27B1 gene are associated with multiple sclerosis.

OBJECTIVE: Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering. METHODS: We performed whole exome sequencing to further understand the heightened prevalence of MS in these families. RESULTS: Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)). INTERPRETATION: A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.

Integrative network analysis of nineteen brain regions identifies molecular signatures and networks underlying selective regional vulnerability to Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive cognitive impairment and neurodegeneration. However, despite extensive clinical and genomic studies, the molecular basis of AD development and progression remains elusive. METHODS: To elucidate molecular systems associated with AD, we developed a large scale gene expression dataset from 1053 postmortem brain samples across 19 cortical regions of 125 individuals with a severity spectrum of dementia and neuropathology of AD. We excluded brain specimens that evidenced neuropathology other than that characteristic of AD. For the first time, we performed a pan-cortical brain region genomic analysis, characterizing the gene expression changes associated with a measure of dementia severity and multiple measures of the severity of neuropathological lesions associated with AD (neuritic plaques and neurofibrillary tangles) and constructing region-specific co-expression networks. We rank-ordered 44,692 gene probesets, 1558 co-expressed gene modules and 19 brain regions based upon their association with the disease traits. RESULTS: The neurobiological pathways identified through these analyses included actin cytoskeleton, axon guidance, and nervous system development. Using public human brain single-cell RNA-sequencing data, we computed brain cell type-specific marker genes for human and determined that many of the abnormally expressed gene signatures and network modules were specific to oligodendrocytes, astrocytes, and neurons. Analysis based on disease severity suggested that: many of the gene expression changes, including those of oligodendrocytes, occurred early in the progression of disease, making them potential translational/treatment development targets and unlikely to be mere bystander result of degeneration; several modules were closely linked to cognitive compromise with lesser association with traditional measures of neuropathology. The brain regional analyses identified temporal lobe gyri as sites associated with the greatest and earliest gene expression abnormalities. CONCLUSIONS: This transcriptomic network analysis of 19 brain regions provides a comprehensive assessment of the critical molecular pathways associated with AD pathology and offers new insights into molecular mechanisms underlying selective regional vulnerability to AD at different stages of the progression of cognitive compromise and development of the canonical neuropathological lesions of AD.

Endogenous neuroprotection: hamartin modulates an austere approach to staying alive in a recession.

Tuberous sclerosis complex 1 (hamartin) is an effective endogenous neuroprotectant. Understanding the endogenous mechanism for neuroprotection mediated by hamartin may afford a novel approach to effective treatment of neurological diseases such as stroke, neurodegenerative diseases, and epilepsy, with possible applications to nonneurological conditions.

Exome sequencing identifies a novel multiple sclerosis susceptibility variant in the TYK2 gene.

OBJECTIVE: To identify rare variants contributing to multiple sclerosis (MS) susceptibility in a family we have previously reported with up to 15 individuals affected across 4 generations. METHODS: We performed exome sequencing in a subset of affected individuals to identify novel variants contributing to MS risk within this unique family. The candidate variant was genotyped in a validation cohort of 2,104 MS trio families. RESULTS: Four family members with MS were sequenced and 21,583 variants were found to be shared among these individuals. Refining the variants to those with 1) a predicted loss of function and 2) present within regions of modest haplotype sharing identified 1 novel mutation (rs55762744) in the tyrosine kinase 2 (TYK2) gene. A different polymorphism within this gene has been shown to be protective in genome-wide association studies. In contrast, the TYK2 variant identified here is a novel, missense mutation and was found to be present in 10/14 (72%) cases and 28/60 (47%) of the unaffected family members. Genotyping additional 2,104 trio families showed the variant to be transmitted preferentially from heterozygous parents (transmitted 16: not transmitted 5; χ(2) = 5.76, p = 0.016). CONCLUSIONS: Rs55762744 is a rare variant of modest effect on MS risk affecting a subset of patients (0.8%). Within this pedigree, rs55762744 is common and appears to be a modifier of modest risk effect. Exome sequencing is a quick and cost-effective method and we show here the utility of sequencing a few cases from a single, unique family to identify a novel variant. The sequencing of additional family members or other families may help identify other variants important in MS.

No evidence for an effect of DNA methylation on multiple sclerosis severity at HLA-DRB1*15 or HLA-DRB5.

Multiple sclerosis (MS) is a complex neurological disease with huge variability in disease outcome. The majority of MS genetic susceptibility is determined by major histocompatibility complex (MHC) alleles, in particular haplotypes carrying HLA-DRB1*1501. HLA-DRB1*1501 also affects the clinical outcome of the disease and animal research has suggested that HLA-DRB5 interacts with HLA-DRB1*1501 to influence disease severity. We used an extremes-of-outcome design with 48 benign and 20 malignant MS patients to assess whether or not DNA methylation at HLA-DRB1*1501 and/or HLA-DRB5 also contributes to MS phenotypic heterogeneity. We found no significant effect of DNA methylation across HLA-DRB1*1501 and HLA-DRB5 on severity, although we cannot rule out time- or tissue-specific effects of DNA methylation.

Heterogeneity in multiple sclerosis: scratching the surface of a complex disease.

Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these "MS subtypes" should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research.