From University of Manchester: “Major cause of dementia discovered”

U Manchester bloc

University of Manchester

12 December 2017
Michael Addelman
Media Relations Officer: Biology, Medicine, and Health
michael.addelman@manchester.ac.uk
+44 (0)161 275 2111
+44 (0)7717 881567

1
A montage of three images of single striatal neurons transfected with a disease-associated version of huntingtin, the protein that causes Huntington’s disease. Nuclei of untransfected neurons are seen in the background (blue). The neuron in the center (yellow) contains an abnormal intracellular accumulation of huntingtin called an inclusion body (orange). Credit: Wikipedia/ Creative Commons Attribution 3.0 Unported license. MedicalXpress.com

An international team of scientists have confirmed the discovery of a major cause of dementia, with important implications for possible treatment and diagnosis.
Professor Garth Cooper from The University of Manchester, who leads the Manchester team, says the build-up of urea in the brain to toxic levels can cause brain damage – and eventually dementia.
The work follows on from Professor Cooper’s earlier studies, which identified metabolic linkages between Huntington’s, other neurodegenerative diseases and type-2 diabetes.
The team consists of scientists from The University of Manchester, the University of Auckland, AgResearch New Zealand, the South Australian Research and Development Institute, Massachusetts General Hospital and Harvard University.

The latest paper by the scientists, published today in the PNAS, shows that Huntington’s Disease – one of seven major types of age-related dementia – is directly linked to brain urea levels and metabolic processes.

Their 2016 study revealing that urea is similarly linked to Alzheimer’s, shows, according to Professor Cooper, that the discovery could be relevant to all types of age-related dementias.

The Huntington’s study also showed that the high urea levels occurred before dementia sets in, which could help doctors to one day diagnose and even treat dementia, well in advance of its onset.
Urea and ammonia in the brain are metabolic breakdown products of protein. Urea is more commonly known as a compound which is excreted from the body in urine. If urea and ammonia build up in the body because the kidneys are unable to eliminate them, for example, serious symptoms can result.

Professor Cooper, who is based at The University of Manchester’s Division of Cardiovascular Sciences, said: “This study on Huntington’s Disease is the final piece of the jigsaw which leads us to conclude that high brain urea plays a pivotal role in dementia.

“Alzheimer’s and Huntington’s are at opposite ends of the dementia spectrum – so if this holds true for these types, then I believe it is highly likely it will hold true for all the major age-related dementias.

“More research, however, is needed to discover the source of the elevated urea in HD, particularly concerning the potential involvement of ammonia and a systemic metabolic defect.
“This could have profound implications for our fundamental understanding of the molecular basis of dementia, and its treatability, including the potential use of therapies already in use for disorders with systemic urea phenotypes.”

Dementia results in a progressive and irreversible loss of nerve cells and brain functioning, causing loss of memory and cognitive impairments affecting the ability to learn. Currently, there is no cure. The team used human brains, donated by families for medical research, as well as transgenic sheep in Australia.

Manchester members of the team used cutting-edge gas chromatography mass spectrometry to measure brain urea levels. For levels to be toxic urea must rise 4-fold or higher than in the normal brain says Professor Cooper.

He added: “We already know Huntington’s Disease is an illness caused by a faulty gene in our DNA – but until now we didn’t understand how that causes brain damage – so we feel this is an important milestone.

“Doctors already use medicines to tackle high levels of ammonia in other parts of the body Lactulose – a commonly used laxative, for example, traps ammonia in the gut. So it is conceivable that one day, a commonly used drug may be able to stop dementia from progressing. It might even be shown that treating this metabolic state in the brain may help in the regeneration of tissue, thus giving a tantalising hint that reversal of dementia may one day be possible.”

Professor Cooper expresses his thanks to all the families of patients with Huntington’s disease in New Zealand who so generously supported this research through the donation of brain tissue to the Neurological Foundation of New Zealand Douglas Human Brain Bank in the Centre for Brain Research.

This work was supported by the CHDI Foundation (A-8247) and Brain Research New Zealand.
The paper ‘Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases’ is available on request
Other Manchester-based scientists who made important contributions are Dr Stefano Patassini and Dr Jingshu Xu.

Relevant papers include:
Graded perturbations of metabolism in multiple regions of human brain in Alzheimer’s disease: Snapshot of a pervasive metabolic disorder. Biochimica et Biophysica Acta (2016)
Identification of elevated urea as a severe, ubiquitous metabolic defect in the brain of patients with Huntington’s disease. Biochemical and Biophysical Research Communications (2015)
Metabolite mapping reveals severe widespread perturbation of multiple metabolic processes in Huntington’s disease human brain. Biochimica et Biophysica Acta (2016)
Elevation of brain glucose and polyol-pathway intermediates with accompanying brain-copper deficiency in patients with Alzheimer’s disease: metabolic basis for dementia. Scientific Reports (2016)
Evidence for widespread, severe brain copper deficiency in Alzheimer’s dementia. Metallomics. (2017)
Proteomic Analysis of the Human Brain in Huntington’s Disease Indicates Pathogenesis by Molecular Processes Linked to other Neurodegenerative Diseases and to Type-2 Diabetes. Journal of Huntington’s Disease (2013)
Proteomic analysis of the brain in Alzheimer’s disease: Molecular Phenotype of a complex disease process. Proteomics (2001)

See the full article here .

Please help promote STEM in your local schools.

STEM Icon

Stem Education Coalition

U Manchester campus

The University of Manchester (UoM) is a public research university in the city of Manchester, England, formed in 2004 by the merger of the University of Manchester Institute of Science and Technology (renamed in 1966, est. 1956 as Manchester College of Science and Technology) which had its ultimate origins in the Mechanics’ Institute established in the city in 1824 and the Victoria University of Manchester founded by charter in 1904 after the dissolution of the federal Victoria University (which also had members in Leeds and Liverpool), but originating in Owens College, founded in Manchester in 1851. The University of Manchester is regarded as a red brick university, and was a product of the civic university movement of the late 19th century. It formed a constituent part of the federal Victoria University between 1880, when it received its royal charter, and 1903–1904, when it was dissolved.

The University of Manchester is ranked 33rd in the world by QS World University Rankings 2015-16. In the 2015 Academic Ranking of World Universities, Manchester is ranked 41st in the world and 5th in the UK. In an employability ranking published by Emerging in 2015, where CEOs and chairmen were asked to select the top universities which they recruited from, Manchester placed 24th in the world and 5th nationally. The Global Employability University Ranking conducted by THE places Manchester at 27th world-wide and 10th in Europe, ahead of academic powerhouses such as Cornell, UPenn and LSE. It is ranked joint 56th in the world and 18th in Europe in the 2015-16 Times Higher Education World University Rankings. In the 2014 Research Excellence Framework, Manchester came fifth in terms of research power and seventeenth for grade point average quality when including specialist institutions. More students try to gain entry to the University of Manchester than to any other university in the country, with more than 55,000 applications for undergraduate courses in 2014 resulting in 6.5 applicants for every place available. According to the 2015 High Fliers Report, Manchester is the most targeted university by the largest number of leading graduate employers in the UK.

The university owns and operates major cultural assets such as the Manchester Museum, Whitworth Art Gallery, John Rylands Library and Jodrell Bank Observatory which includes the Grade I listed Lovell Telescope.