In a recent article published in Neurology, the Dementia with Lewy Bodies (DLB) Consortium published new consensus research criteria for prodromal DLB, or DLB prior to the onset of dementia. These new criteria have the potential to significantly impact clinical trials and the development of drugs to treat, delay, or prevent DLB.
Dementia with Lewy bodies (DLB), the most common form of dementia after Alzheimer’s disease, is characterized by progressive cognitive decline with fluctuating alertness, parkinsonism, and psychiatric disturbance. Many patients also experience sleep disruptions, visual hallucinations, and other psychotic symptoms. It is believed that DLB symptoms are related to the aggregation of a misfolded protein, alphasynuclien, into the eponymous Lewy bodies which disrupt neuronal functioning. Lewy bodies in the brainstem are thought to cause motor disturbances, while Lewy bodies in the occipital cortext and frontal lobes are related to visuospatial deficits and executive dysfunction respectively. Alzheimer’s neuropathology, including accumulation of amyloid-beta plaque and neurofibrillary tangles are also found in many patients with DLB and associated with cognitive deficits.
In 2017, the DLB Consortium published a consensus report outlining diagnostic criteria for DLB. The first core criterion was dementia. While establishing cognitive deficits as central to DLB, this had the unfortunate effect of delaying formal diagnosis of many patients who evinced the hallmark constellation of neuropsychiatric disturbances, but had not yet shown the magnitude of decline in cognition or functional independence requisite for dementia. As such, timely intervention with disease-modifying and neuroprotective therapies in DLB clinical trials was limited.
Criteria for Prodromal DLB
In 2020, new research consensus criteria for prodromal DLB was published in Neurology. This landmark publication acknowledges characteristic symptoms that may present years before the full DLB syndrome can be diagnosed. Prodromal DLB includes not only cognitive deficits, but motor signs and symptoms, sleep disorders, autonomic dysfunction, and neuropsychiatric disturbance. These clinical manifestations can begin as early as 15 years before formal diagnostic criteria for dementia are met. Three variants of prodromal DLB are described—mild cognitive impairment (MCI-LB), delirium onset (delirium onset-DLB), and psychiatric onset (psychiatric onset-DLB). The consortium proposes diagnostic criteria for probable and possible MCI-LB intended for use in research settings. The research criteria for MCI-LB includes essential elements, core clinical features, and proposed biomarkers.
Impact on Clinical Trials and Development of Therapies for DLB
Identifying patients in the very early stages of any neurodegenerative disease is critically important for developing effective therapies which can be implemented before the extent of brain injury is unrecoverable. The new research criteria for prodromal DLB allows the timely identification of patients at risk for transitioning to the full DLB dementia syndrome. By enrolling these early staged patients into clinical trials, there is the potential to slow the disease progression and prevent the onset of dementia. Because patients would be enrolled at a point in illness when they are more capable of adhering to study procedures, retention is likely to be higher as well in trials focused on prodromal DLB. This all bodes well for future clinical trials in DLB, enabling standardization across studies and early intervention in a clinically challenging neurodegenerative disease and bringing hope to patients with DLB and their families.
Lewy body dementia. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/lewy-body-dementia/symptoms-causes/syc-20352025
Mckeith, I. G., Boeve, B. F., Dickson, D. W., Halliday, G., Taylor, J., Weintraub, D., . . . Kosaka, K. (2017). Diagnosis and management of dementia with Lewy bodies. Neurology, 89(1), 88-100. doi:10.1212/wnl.0000000000004058
Mckeith, I. G., Ferman, T. J., Thomas, A. J., Blanc, F., Boeve, B. F., Fujishiro, H., . . . Tiraboschi, P. (2020). Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology, 94(17), 743-755. doi:10.1212/wnl.0000000000009323