Tag Archives: Neurological

Small Pollution Particles May Pass Directly into the Brain through the Snout

Yes, they appear to be able to follow the pathway used by smell neurons and thus pass directly from the olfactory membrane into the brain, i.e. not going via the lung and bloodstream. Experiments in rodents using radio-labelled nano-particles show that very small particles really can penetrate directly through the roof of the nose and pass into the brain along olfactory neurons.[1] Here these particles set in motion an inflammatory process, which activates micro-glia (brain type macrophages), which attack neurons and lead to amyloid deposits – the hall mark of dementia. People who are exposed to particles have a high risk of dementia,[2] and animals randomised to be exposed (or not) to pollution particles acquire brain amyloid and manifest cognitive decline. So there you have it – there is growing and quite compelling evidence that pollution particles are bad news for humans and other animals. It is time to act – phase out diesel cars, incentivise car manufacturers to clean up emissions, gradually increase tax on cars/lorries/fuels, incentivise cycling in cities (and make it safer), and build rail lines. But none of this will happen without public support so proselytise and increase susceptibility to the message by increasing science teaching in schools. In the end, lots of things come back to the intellectual sophistication of the average citizen. In the meantime I suspect that an increasing proportion of people will adopt face masks, although I do not know how effective they are in trapping particles.

— Richard Lilford, CLAHRC WM Director

References:

  1. Underwood E. The Polluted Brain. Science. 2017; 355(6323): 342-5.
  2. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia, Parkinson’s disease, and multiple sclerosis: a population-based cohort study. Lancet. 2017; 389(10070): 718-26.

Okay Then, There is a Fourth Period of Whole-Scale Synaptic Pruning in the Grey Matter of the Brain

This News Blog has frequently discussed synaptic pruning [1] [2] – a process that occurs in the foetus at mid-gestation, children at around the age of two, and in late adolescence. Abnormalities in neural synaptic pruning are associated with diseases, such as schizophrenia and autism.[3] It turns out that there is another period of synaptic pruning – during pregnancy. Functional MRI shows that many areas of grey matter shrink in pregnancy. Greater pruning is associated with higher scores on standard questionnaires measuring a mother’s attachment to her baby.[4] More brain does not necessarily mean better brain.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands News Blog. 11 March 2016.
  2. Lilford RJ. A Fascinating Account of the Opening Up of an Area of Scientific Enquiry. NIHR CLAHRC West Midlands News Blog. 11 November 2016.
  3. van Spronsen M, Hoogenraad CC. Synapse Pathology in Psychiatric and Neurologic Disease. Curr Neurol Neurosci Rep. 2010; 10(3): 207-14.
  4. Hoekzema E, Barba-Müller E, Pozzobon C, et al. Pregnancy leads to long-lasting changes in human brain structure. Nature Neurosci. 2016.

A Fascinating Account of the Opening Up of an Area of Scientific Enquiry

News Blog readers may have seen previous posts on synaptic pruning.[1] Synaptic pruning involves the elimination of synapses with weak connections between brain neurons. Pruning is especially exuberant after periods of rapid neuronal multiplication (in mid-gestation, around the age of two years, and in late adolescence). Over-exuberant synaptic pruning is associated with schizophrenia. It may also play a crucial role in degenerative brain diseases, such as Alzheimer’s, and in people with memory loss after West Nile fever. The biochemical trigger arises from products of the complement cascade. Astrocytes induce neuronal cells to make the protein C1q, which triggers the complement cascade in neurons. Complement factors, such as C3 attach to weak synapses, and micro-glia (the macrophages of the brain) then ingest the tagged synapses. This process can be visualised by staining living brain cells – bits of synapse end up in the micro-glia. A genetic predisposition to over-express certain complement components increases the risk of schizophrenia markedly, as reported in a previous post.[2] As brains age C1q levels increase four-fold, and this likely predisposes to degenerative diseases, such as Alzheimer’s. Drugs to dampen down this cascade are entering clinical trials. For a lively account if the human story behind one of the leading scientists involved in unravelling this story, see an article by Emily Underwood.[3]

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Psychiatry Comes of Age. NIHR CLAHRC West Midlands. 11 March 2016.
  2. Lilford RJ. Molecular Diagnostic Testing, Including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder. NIHR CLAHRC West Midlands. 23 October 2015.
  3. Underwood E. This woman may know a secret to saving the brain’s synapses. Aug 18 2016.

Psychiatry Comes of Age

In a recent post the CLAHRC WM Director opined that psychiatry was taking its first reductive steps – we are starting to understand the neurochemical mechanisms behind diseases that appear in the mind. Well our toddler has started to run and the new era has been ushered in with a brilliant recent publication in Nature.[1] The story starts, as it increasingly does in modern science, with a large collaborative effort – in this case the international Psychiatric Genomics Consortium, which carries out genetic association studies. Their Biobank harbours 39,000 cases of schizophrenia and 45,000 controls. There are many genetic polymorphisms across the genome that are associated with schizophrenia – about 100 in fact, as mentioned in a previous post. But one constellation of polymorphisms stands out in terms of the strength of its association with schizophrenia. This constellation resides in the HLA gene cluster. Genes in this cluster encode proteins that help the immune system identify foreign antigens, such as those found on the cell surface of microbes or transplanted tissue. Polymorphisms in the HLA cluster are associated with autoimmune disease, meaning that the immune system has mistakenly identified an antigen on a normal host cell for attack. Does this mean that schizophrenia might be an autoimmune disease? Well, sometimes perhaps (see below), but there is another mechanism by which HLA variants may predispose to this devastating disease. It turns out that the part of the HLA complex most closely associated with schizophrenia is the gene responsible for one of the complement proteins known as complement component 4. And this molecule is not just active in eliminating pathogens and cellular debris – it also affects nerve cells by directly accelerating the pruning of synapses. Synaptic pruning is a normal part of adolescent brain remoulding, but excessive pruning, associated with over-active complement 4, features as part of the pathogenesis in many cases of schizophrenia.[1] Enter NIHR CLAHRC East of England Director Peter Jones. Jones hypothesises that around 10% of cases of acute onset schizophrenia result from an acute autoimmune brain syndrome. He is testing this hypothesis by means of a RCT involving immunosuppression. Presumably it is no co-incidence that some cases of schizophrenia result from a form of autoimmune disease, and that genes in the HLA constellation are so frequently associated with schizophrenia. If so, much of the damage may have been done when the acute brain syndrome appears – we may need to look for an earlier, more tightly targeted therapy, and we suspect that preventing complement-mediated damage will play a role. Incidentally, this is a further example of massive scientific achievement emanating from an international collaborative effort, rather than the genius of just one individual. The future prominent scientist will increasingly be the one with the social skills to engineer a prominent place for herself on the committees that shape protocols and scientific papers, such as the Global Burden of Disease project discussed in a recent post.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Sekar A, Bialas AR, de Rivera H, et al. Schizophrenia risk from complex variation of complement component 4. Nature. 2016; 530: 177-83.

Molecular Diagnostic Testing, including Whole-Exome Sequencing, in Children with Autism Spectrum Disorder

CLAHRC WM News Blog features articles of generic, rather than specific, interest. The general interest here lies in the use of molecular techniques to unravel the mechanisms of diseases, especially neurological diseases, that are inaccessible to study in other ways.
A study of 258 consecutively ascertained children with ASD was recently reported in JAMA.[1] The incidence of genetic abnormalities was low (about 6%) in ASD children with no morphological abnormalities, but unsurprisingly reached much higher levels (38%) when complex morphological abnormalities were present. To the CLAHRC WM Director this finding suggests that ASD, when not associated with atypical physical features, is seldom caused by embryonic de novo or inherited genetic disorder. But could it be caused by propagation of a clone of neurons with a new mutation derived during the first wave of brain remodelling in utero?[2] [3]

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Tammimies K, Marshall CR, Walker S, et al. Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children with Autism Spectrum Disorder. JAMA. 2015; 314(9): 895-903.
  2. Lilford R. An hypothesis on the cause of many chronic neurological conditions, such as schizophrenia and Alzheimer’s disease. January 18 2013.
  3. Lilford R. Biological mechanism of generalised brain disease such as Alzheimer’s disease and schizophrenia. March 1 2013.