Disease modification and Neuroprotection in neurodegenerative disorders

Abstract

Background: Disease modifying therapies (DMTs) are urgently needed for neurodegenerative diseases (NDD) such as Alzheimer's disease (AD) and many other disorders characterized by protein aggregation and neurodegeneration. Despite advances in understanding the neurobiology of NDD, there are no approved DMTs.

Discussion: Defining disease-modification is critical to drug-development programs. A DMT is an intervention that produces an enduring change in the trajectory of clinical decline of an NDD by impacting the disease processes leading to nerve cell death. A DMT is neuroprotective, and neuroprotection will result in disease modification. Disease modification can be demonstrated in clinical trials by a drug-placebo difference in clinical outcomes supported by a drug-placebo difference on biomarkers reflective of the fundamental pathophysiology of the NDD. Alternatively, disease modification can be supported by findings on a staggered start or delayed withdrawal clinical trial design. Collecting multiple biomarkers is necessary to support a comprehensive view of disease modification.

Conclusion: Disease modification is established by demonstrating an enduring change in the clinical trajectory of an NDD based on intervention in the fundamental pathophysiology of the disease leading to nerve cell death. Supporting data are collected in clinical trials. Effectively defining a DMT will assist in NDD drug development programs.

Keywords: Alzheimer’s disease; Amyotropic lateral sclerosis; Corticobasal degeneration; Disease modification; Disease modifying therapy; Frontotemporal dementia; Multiple system atrophy; Progressive supranuclear palsy.

Fig. 1

The conceptual framework for disease-modification in neurodegenerative disorders included neuroprotection preventing neurodegeneration with biomarker and clinical support for a disease-modifying therapy (DMT)

Fig. 2

Biomarkers of neurodegenerative disorders (a) and of Alzheimer’s disease (b). The exact order of the cascade of events from Aß production to cell death is not fully determined (Aß – amyloid ß protein; AD – Alzheimer’s disease; ASL – arterial spin labeling; DTI – diffusion tensor imaging; FDG – fluoroeoxyglucose; fMRI functional magnetic resonance imaging; NF-L – neurofilament light; PET – positron emission tomography; p-tau – phosphorylated tau protein; Q-EEG – quantitative electroencephalography; SILK – stable isotope-labeled kinetics). *The regional pattern of these changes may be specific to the neurodegenerative disease

Fig. 3

Delayed start design (a). The delayed treatment group (3) does not catch up with the early treatment group (2). (1) is the untreated, placebo group. Staggered withdrawal design (b). The withdrawn group (3) does not decline to the level of the placebo group (1)