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Multimorbidity in the ageing human brain: lessons from neuropathological assessment

9 June 2021

A webinar hosted by Bristol Neuroscience given by Dr Kirsty McAleese at Newcastle University on 8 June 2021 is now available to watch online.

Age-associated dementias are neuropathologically characterized by the identification of hallmark intracellular and extracellular deposition of proteins, i.e., hyperphosphorylated-tau, amyloid-β, and α-synuclein, or cerebrovascular lesions. The neuropathological assessment and staging of these pathologies allows for a diagnosis of a distinct disease, e.g., amyloid-β plaques and hyperphosphorylated tau pathology in Alzheimer's disease. Neuropathological assessment in large scale cohorts, such as the UK’s Brains for Dementia Research (BDR) programme, has made it increasingly clear that the ageing brain is characterized by the presence of multiple age-associated pathologies rather than just the ‘pure’ hallmark lesion as commonly perceived. These additional pathologies can range from low/intermediate levels, that are assumed to have little if any clinical significance, to a full-blown mixed disease where there is the presence of two distinct diseases. 

In our recent paper,, using the BDR cohort, we investigated the frequency of multimorbidity and specifically investigated the impact of additional low-level pathology on cognition. In this study, of 670 donated post-mortem brains, we found that almost 70% of cases exhibited multimorbidity and only 22% were considered a pure diagnosis. Importantly, no case of Lewy Body dementia or vascular dementia was considered pure. A key finding is that the presence of low levels of additional pathology increased the likelihood of having mild dementia vs mild cognitive impairment by almost 20-fold, indicating low levels of additional pathology do impact the clinical progression of a distinct disease. 

Given the high prevalence and the potential clinical impact, cerebral multimorbidity should be at the forefront of consideration in dementia research.

Kirsty McAleese, Alzheimer’s Society Fellow, Newcastle University

I completed my PhD in neurodegenerative pathology at Newcastle University in 2014. I have since continued my research into white matter changes in Alzheimer’s disease as a research associate and recently appointed Research Fellow funded by the Alzheimer's Society. My area of expertise is neurodegenerative pathology. 

I am based in the Translational and Clinical Research Institute at Newcastle. My current research project is investigating the mechanisms underlying white matter damage in the normal ageing human brain and in patients with Alzheimer's disease using post mortem brain tissue. White matter damage can be visualised on MRI scans during life and can influence dementia diagnosis, therefore, clear understanding of the underlying cause is crucial for the correct dementia diagnosis, treatments and future drug development. This is a collaborative project with UC Davis, California.

In addition, my research focus includes i) digital quantitative assessment of age-associated neuropathology, ii) the frequency, severity and patterns of cerebral multimorbidity in the ageing human brain, iii) the assessment and clinical impact of Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) in age-associated neurodegenerative diseases. 

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