Dr Gerry Morrow shares his thoughts on the current state of play when it comes to the early diagnosis of neurodegenerative disorders, and asks the questions, can we screen, and should we screen?
The World Health Organisation has estimated that 47.5 million people worldwide have dementia and there are 7.7 million new cases each year. In the UK in 2014, there were an estimated 835,000 people living with dementia. By 2051, this number is expected to increase to over 2 million. About 29–76% of people with dementia or probable dementia in primary care are estimated to be undiagnosed.
Parkinson’s disease is another common neurodegenerative condition in elderly people. There are about 137,000 people living with Parkinson’s disease in the UK. The prevalence of Parkinson’s disease increases with age – the prevalence is 4–5 per 100,000 people in people aged 30–39 years, compared with 1,696 per 100,000 people aged 80–84 years.
The disease burden for patients, carers, relatives and the wider health economy is enormous and increasing. This in tandem, with the fact that these conditions are life-limiting has resulted in a clinical imperative to provide an earlier diagnosis to provide improved disease-modifying therapeutic options.
It is thought that many neurodegenerative disorders may share a common pathophysiological aetiology through a problem with abnormal protein transport synthesis and deposition, mitochondrial dysfunction, and defects in intracellular trafficking, causing subsequent plaque formation and neurofibrillary entanglement. This then presents both a problem for delineating a definitive sub-type disorder diagnosis but also a potential window for early diagnosis and interventional therapeutic hope for the future.
The challenge of making a diagnosis of dementia?
It can be extremely difficult to make a definitive clinical diagnosis of dementia. The reasons for this are that it presents variably in different individuals and usually has an insidious onset with non-specific signs and symptoms. In practice, diagnosis is mainly based on an expert clinical assessment and on neuroimaging. Neuroimaging may assist in excluding some cerebral pathologies but may not be conclusive. The uncertainty around the time of a possible diagnosis is often the most challenging for patients and their relatives. The fear of inexorable cognitive decline and reduced life expectancy with no prospect of curative therapeutic solutions is often viewed as being as problematic as the disease process itself.
What can we then do to provide an early accurate diagnosis?
Newer diagnostic tools have been discussed and employed in research settings for some years to assist with the diagnosis of neurodegenerative disorders. These include the use of biomarkers in blood and cerebrospinal fluid (CSF), genomic sequencing, and bioinformatic data. There is potential for each of these approaches or a combination. There are however problems with each.
Blood biomarkers would seem the simplest and cheapest option. Despite the initial optimism of their potential this has failed to provide reliable, sensitive or accurate diagnostic information for clinicians.
CSF biomarkers for amyloid beta 42 and tau certainly are more accurate, but sampling CSF is an invasive procedure with the potential for adverse effects. Genomic sequencing may prove useful in the future, but this is an expensive technique with significant limitations which include the accuracy of defining benign from pathological genetic variation. For example, some researchers estimate that in in a single individual genome up to 11,000 non-synonymous genetic variants exist.
Bioinformatics has raised hopes once more of an early diagnosis. Specifically, analysing computer keystrokes and digital phenotypes of people using internet search engines. This work provided a large database proving possible early diagnostic predictors of cognitive decline and functional debility, such as velocity and jerkiness of mouse movements.
Should we screen for neurodegenerative disorders?
Any potential screening approach should be informed by Wilson’s criteria. These include the concepts that:
- There should be a test that is easy to perform and interpret, acceptable, accurate, reliable, sensitive and specific;
- There should be an accepted treatment recognised for the disease;
- Treatment should be more effective if started early.
Clearly, we are not at this stage for dementia, Parkinson’s disease or other neurodegenerative disorders. The tests currently at our disposal are expensive, invasive, rely on non-validated databases and are not sensitive or specific enough for reliable point of care testing.
What can we expect in the future?
Future diagnostic tools will need to provide more reliable benefits for patients and clinicians. We hope that we may be able to differentiate benign from pathological variants both from a genetic and bioinformatics perspective. We also hope that simpler blood testing will find its way into the primary care environment to allow for more rapid diagnosis and that this test will lay the groundwork for a potential therapeutic intervention.
A leading healthcare professional, Dr Gerry Morrow has over twenty years’ experience working as a GP and a proven track record of advising and working with NICE, Royal Colleges, Academic Health Science Networks and senior NHS bodies. As the Medical Director of Clarity Informatics, one of Gerry’s responsibilities is the production and Clarity’s clinical guidance – Prodigy – which forms the clinical content of NICE’s Clinical Knowledge Summaries (CKS) service and is designed to assist clinicians to treat common conditions and symptoms.
1 Baldacci F et al Blood-based biomarker screening with agnostic biological definitions for an accurate diagnosis within the spectrum of neurodegenerative diseases Methods in Molecular Biology, vol. 1750.
2 Gonzales-Cuyar LF et al Role of cerebrospinal fluid and plasma biomarkers in the diagnosis of neurodegenerative disorders and mild cognitive impairment doi 10.1007/s11910-011-0212-0.
3 Guerreiro R et al A comprehensive assessment of benign genetic variability for neurodegenerative disorders BioRxiv doi http://dx.doi.org/10.1101/270686
4 Reijs BLR Cognitive Correlates of Cerebrospinal Fluid Markers for Alzheimer’s disease.
5 White RW et al Detecting neurodegenerative disorders from web search signals Nature Partner Journals Digital Medicine (2018) 1:8; doi: 10.1038/s4176-018-0016-6.
6 Yin-Yu S et al The role of gene variants in the pathogenesis of neurodegenerative disorders as revealed by next generation sequencing studies: a review doi /10.1186/s40035-017-0098-0
Dr Gerry Morrow
Tel: +44 (0)845 113 1000