Jeffrey Cummings, MD, ScD
Director, Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas
Disclosure: Jeffrey Cummings has provided consultation to Axovant, biOasis Technologies, Biogen, Boehinger-Ingelheim, Bracket, Dart, Eisai, Genentech, Grifols, Intracellular Therapies, Kyowa, Eli Lilly, Lundbeck, Medavante, Merck, Neurotrope, Novartis, Nutricia, Orion, Otsuka, Pfizer, Probiodrug, QR, Resverlogix, Servier, Suven, Takeda, Toyoma, and United Neuroscience companies.
Jeffrey Cummings, MD, ScD
As Neurology Reviews celebrates its 25th anniversary, we take this opportunity to look back and to look ahead in the area of dementia care and research. Most dementia research has focused on Alzheimer’s disease, although there have been important evolutions in the diagnosis, pathology, and potential interventions for frontotemporal dementia spectrum disorders, dementia with Lewy bodies, Parkinson’s disease dementia, and vascular dementia.
Alzheimer’s Disease
Twenty-five years ago—coinciding with the inauguration of Neurology Reviews—the first treatment for Alzheimer’s disease, the cholinesterase inhibitor tacrine, was approved by the FDA. Tacrine had many limitations, including a short half-life and a propensity to cause hepatotoxicity, but it represented an historical breakthrough in transforming an untreatable disease into a treatable one. The approval energized the field and gave hope to thousands of patients with Alzheimer’s disease dementia.
Tacrine was followed by other cholinesterase inhibitors and memantine in the next decade, with five drugs approved by the end of 2003. Unfortunately, no new agents have been approved for the treatment of Alzheimer’s disease since that fertile period.1 Tremendous efforts are now being devoted to developing disease-modifying treatments for Alzheimer’s disease and other dementias. There are promising preliminary observations for immunotherapies that remove amyloid-beta protein from the brain and stabilize cognitive decline.2 Progress in the development of disease-modifying treatments will transform the field, requiring much of the health care system and insurance companies, but offering an improved quality of life for millions of patients with Alzheimer’s disease.
Previous Advances
A major advance in understanding Alzheimer’s disease is the discovery that the disease begins with amyloid accumulation in mid-life, approximately 15 years before the onset of cognitive decline.3 The advent of amyloid imaging has allowed the visualization of fibrillar amyloid-comprising Alzheimer-type neuritic plaques in the brain of the living person. Scans become positive 15 years prior to the emergence of mild cognitive impairment (MCI) and progression to Alzheimer’s disease dementia. If one is destined to develop MCI at age 75, the scan would be positive by approximately age 60. CSF levels of amyloid beta decline simultaneously as the protein is trapped in the brain, thus resulting in positive amyloid imaging. More recently, findings from tau protein imaging have begun to remodel our understanding of the role of tau in Alzheimer’s disease. Tau imaging correlates with the emergence of symptoms in the MCI phase of Alzheimer’s disease.4 Tau correlates with cognitive decline; positive amyloid imaging does not.
Future Challenges
Looking to the future, it is likely that companion biomarkers such as amyloid and tau imaging will be approved for clinical use. They will enable neurologists to identify the patients whose brain changes match the mechanism of action of the intended treatment (eg, positive tau imaging for those to receive anti-tau therapy and positive amyloid imaging for individuals intended to receive anti-amyloid therapy).
Anticipated directions of therapy development include treatment of individuals before the onset of symptoms, phase-specific therapies that respond to the evolving state changes of Alzheimer’s disease, and combination therapies based on the observation that most patients with Alzheimer’s disease harbor multiple types of brain pathology.5 Alzheimer’s disease therapeutics will proceed in the direction of precision medicine with better matching of therapies to the features of the disorder for the individual patient.
The US health care system is unprepared for the advent of disease-modifying treatments for Alzheimer’s disease. Recognition of patients with mild changes, availability of amyloid imaging to support diagnosis and identify therapeutic targets, and the number of infusion centers to administer monoclonal antibodies are all insufficient to respond to the large and growing number of patients with or at risk for Alzheimer’s disease. Transformation of the system’s capacity will be needed as disease-modifying treatments emerge.
Advances in the understanding of frontotemporal dementia have not yet led to a breakthrough therapy. Frontotemporal dementia has been shown to be pathologically heterogeneous, with about half of the patients having an underlying tauopathy, and about half having TDP-43 as the associated aggregated protein.6 A few cases have rarer forms of pathology. Major phenotypes of frontotemporal dementia include behavioral variant frontotemporal dementia, progressive nonfluent aphasia, and semantic dementia. Trials of new candidate therapies are progressing for frontotemporal dementia spectrum disorders, and new treatments are anticipated.
Progress in understanding dementia with Lewy bodies has led to the publication of diagnostic criteria.7 The phenotype of parkinsonism, fluctuating cognition, and visual hallucinations is supported by decreased dopamine uptake on dopamine transporter (DaT) scanning and the presence of REM sleep behavior disorder. Lewy bodies are found in the limbic and neocortex at autopsy; many cases have concomitant amyloid plaques similar to those of Alzheimer’s disease. Parkinson’s disease dementia has many of the same features and is distinguished from dementia with Lewy bodies only by the order of appearance of major symptoms—dementia first in dementia with Lewy bodies, parkinsonism first in Parkinson’s disease dementia. Rivastigmine is approved for the symptomatic treatment of cognitive deficits in Parkinson’s disease dementia, and trials of new therapies are being conducted in Parkinson’s disease dementia and dementia with Lewy bodies. Alpha-synuclein is present in both disorders and is the target of new disease-modifying treatments currently in clinical trials.
Improved understanding of the basic biology of neurodegenerative disease is critically important and must be accelerated. This knowledge will provide the foundation for improved diagnostics and therapeutics essential for responding to the needs of the burgeoning number of patients with these late-life brain disorders.
References
1. Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6(4):37-43.
2. Sevigny J, Chiao P, Bussiere T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature. 2016;537(7618):50-56.
3. Villemagne VL, Burnham S, Bourgeat P, et al. Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 2013;12(4):357-367.
4. Johnson KA, Schultz A, Betensky RA, et al. Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol. 2016;79(1):110-119.
5. James BD, Wilson RS, Boyle PA, et al. TDP-43 stage, mixed pathologies, and clinical Alzheimer’s-type dementia. Brain. 2016;139(11):2983-2993.
6. Lashley T, Rohrer JD, Mead S, Revesz T. Review: an update on clinical, genetic and pathological aspects of frontotemporal lobar degenerations. Neuropathol Appl Neurobiol. 2015;41(7):858-881.
7. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88-100.