Cerebrospinal fluid and positron-emission tomography biomarkers for noradrenergic dysfunction in neurodegenerative diseases: a systematic review and meta-analysis

The noradrenergic system shows pathological modifications in aging and neurodegenerative diseases and undergoes substantial neuronal loss in Alzheimer’s disease and Parkinson’s disease. While a coherent picture of structural decline in post-mortem and in vivo MRI measures seems to emerge, whether this translates into a consistent decline in available noradrenaline levels is unclear. We conducted a meta-analysis of noradrenergic differences in Alzheimer’s disease dementia and Parkinson’s disease using CSF and PET biomarkers. CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol levels as well as noradrenaline transporters availability, measured with PET, were summarized from 26 articles using a random-effects model meta-analysis. Compared to controls, individuals with Parkinson’s disease showed significantly decreased levels of CSF noradrenaline and 3-methoxy-4-hydroxyphenylglycol, as well as noradrenaline transporters availability in the hypothalamus. In Alzheimer’s disease dementia, 3-methoxy-4-hydroxyphenylglycol but not noradrenaline levels were increased compared to controls. Both CSF and PET biomarkers of noradrenergic dysfunction reveal significant alterations in Parkinson’s disease and Alzheimer’s disease dementia. However, further studies are required to understand how these biomarkers are associated to the clinical symptoms and pathology.