The UK Biobank 18 offers a rare opportunity to analyze pre-diagnostic changes across a wide range of sporadic neurodegenerative diseases. 7, 16, 17 It remains unclear whether changes in cognition and physical function in sporadic neurodegenerative diseases are detectable before symptom onset and how long before a diagnosis they are identifiable. 5, 15 However, global cognitive and behavioral functions remain near normal if supported by a reorganization of the brain's functional network.
There is evidence for pre-diagnostic accelerated forgetting in familial AD mutation carriers, 14 whereas apathy and executive dysfunction appear early in individuals who carry mutations for FTD. These studies suggest early pathological changes, but it remains less certain whether this translates into impaired cognition or day-to-day function. 12 There is also evidence for a pre-symptomatic reduction in the monoaminergic nuclei MRI (magnetic resonance imaging) signal. There is indirect evidence that Aβ neuropathology is present several years before symptom onset in sporadic AD and is associated with cognitive decline. The pre-diagnostic phase of sporadic neurodegenerative disease is more challenging to assess. 8 In genetic Alzheimer's disease (AD), CSF and neuroimaging changes may be seen 15 to 25 years before symptom onset. In genetic frontotemporal dementia (FTD), structural brain changes are detectable 10 years before symptom onset, 4- 6 with pre-symptomatic alterations in functional brain network organization 7 and microRNA (miRNA) expression. Studies of genetic dementia cohorts suggest that disease biomarkers change in neurodegenerative diseases years before symptoms are obvious. A screening panel based on cognition and function could be followed by disease-specific biomarkers to further improve risk stratification. We found disease-relevant patterns of pre-diagnostic cognitive and functional impairment and observed a pre-diagnostic linear decline in a number of cognitive and functional measures.įuture Directions: Our approach can form the basis for pre-diagnostic cognitive and functional screening to recruit into trials of disease prevention and disease-modifying therapies for neurodegenerative diseases. Interpretation: We have established an approach to identify cognitive and functional pre-diagnostic markers of neurodegenerative disease years before diagnosis. It is unclear whether early functional or cognitive changes are detectable in sporadic neurodegenerative disease. The pre-diagnostic phase of sporadic neurodegenerative disease has been less well studied. Systematic Review: Studies of genetic dementia cohorts provide evidence for pre-diagnostic changes in disease biomarkers and cognitive function in several genetic neurodegenerative diseases. Identifying pre-diagnostic functional and cognitive changes could improve selection for preventive and early disease-modifying treatment trials. The scale and longitudinal follow-up of UK Biobank participants provides evidence for cognitive and functional decline years before symptoms become obvious in multiple neurodegenerative diseases.
Pre-diagnostic functional impairment and decline were observed in multiple diseases. There was evidence for pre-diagnostic cognitive impairment and decline with time, particularly in AD. The same measures were regressed against time to diagnosis, after adjusting for the effects of age. Cognitive and functional measures in individuals who subsequently developed Alzheimer's disease (AD), Parkinson disease, frontotemporal dementia, progressive supranuclear palsy, dementia with Lewy bodies, or multiple system atrophy were compared against individuals without neurodegenerative diagnoses. However, pre-diagnostic changes in cognition and physical function are poorly understood, especially in sporadic neurodegenerative disease. The pathophysiological processes of neurodegenerative diseases begin years before diagnosis.
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