Challenges and Opportunities in Neurodegeneration
Philip H.C. Kremer & Geert Jan Groeneveld
Abstract
With aging populations in many countries, the prevalence of neurodegenerative diseases is expected to increase in the upcoming decades. Currently, no disease modifying therapies for these conditions exist. Advances in genetics and proteomics have identified novel druggable targets for neurodegenerative diseases. Compounds modulating these targets have recently entered clinical trials. These compounds can be orally administered small drug molecules, intravenously dosed antibodies, intrathecally injected antisense oligonucleotides (ASOs), gene therapies, stem cells or viral vectors. For the development of these compounds to be successful, multiple challenges have to be overcome. In this review we discuss advances in drug development for each of the major neurodegenerative diseases, which, when applied to early phase drug studies, increase the chance of successful clinical development. Here we will limit ourselves to: 1) the use of biomarkers for understanding target and pathway engagement at an early stage of development, 2) novel approaches for increasing blood-brain barrier penetration and 3) advances in understanding cerebrospinal fluid flow dynamics in relation to neurodegeneration and target site distribution for intrathecally administered compounds.
Michael S. Wolfe
Department of Medicinal Chemistry, University of Kansas, Lawrence, Kansas 66045 USA
Abstract
For over 30 years, the amyloid hypothesis of Alzheimer’s disease has dominated this field of biomedical investigation. The hypothesis posits that aggregation of the amyloid β-peptide (Aβ) in the brain triggers a cascade of events that ultimately lead to neurodegeneration and cognitive decline. Early genetic and biochemical evidence supported a critical role of Aβ, particularly the 42-residue form Aβ42: Dominant missense mutations in the substrate (amyloid precursor protein, APP) and enzyme (γ-secretase) that produce Aβ cause early-onset familial Alzheimer’s disease (FAD). Nevertheless, serious gaps remain in understanding pathogenic pathways, and despite intense efforts over many years, effective agents for Alzheimer’s disease have been elusive. Here I discuss recent efforts to elucidate precisely how FAD mutations alter the complex proteolytic processing of APP substrate by γ-secretase, with results suggesting pathogenic triggers other than Aβ42.
Ivan V. Maksimovich
Clinic of Cardiovascular Diseases named after Most Holy John Tobolsky, Building 2, Block 15, 6th Lazenki Str., 119619 Moscow, Russia
Abstract
Background: Alzheimer’s disease (AD) is the world’s number one cerebral neurodegenerative disease. Up to 80% of all dementia cases are due to this disease. AD occurs not only because of impaired metabolism of amyloid beta (Aβ) and tau protein in cerebral tissue, but also in connection with specific disorders of cerebral blood supply, manifested in dyscirculatory angiopathy of Alzheimer’s type (DAAT).
Aims: The present research focuses on the clinical discovery of the sequence of development of dyscirculatory angiopathy of Alzheimer’s type, cerebral atrophy, and dementia in patients with AD and their immediate family members.
Methods: 99 patients were selected for the research, of whom:
Test Group 1
93 (93.94%) suffered from various stages of AD and severity of dementia (age 34-79 (mean age 67): 32 (34.40%) men, 61 (65.59%) women).
Test Group 2
6 (6.06%) children aged 8-12 with a high probability of inheriting AD. Each of them had a parent diagnosed with AD with mild dementia (TDR-1), and a grandparent diagnosed with AD with moderate (TDR-2) or severe dementia (TDR-3). Each child complained of fatigue, memory loss, difficulty in remembering, difficulty in concentrating, and frequent headaches.
Results:
Test Group 1. According to the severity of dementia and atrophic changes in the temporal lobes, the patients were subdivided: preclinical stage TDR-0 – 10 (10.75%) people, mild stage AD TDR-1 – 26 (27.96%) people, moderately severe stage AD TDR-2-40 (43.01%) people, severe AD TDR-3 – 17 (18.28%) people. We identified dyscirculatory angiopathy of Alzheimer’s type in all patients, regardless of their AD stage.
Test Group 2. There were no signs of dementia of cognitive disorders in any case. Initial involutive cerebral changes were detected in all 6 (100%) patients. Phenomena similar to DAAT were detected in all 6 (100%) patients.
Conclusion: Cerebrovascular changes manifested by dyscirculatory angiopathy of Alzheimer’s type, regardless of the stage of the disease, are observed in all patients with AD, as well as in all their young offspring.
These changes affect amyloid beta metabolism in the brain and contribute to its deposition and accumulation in cerebral tissue, which leads to neurodegeneration and AD development.
The data obtained indicate that dyscirculatory angiopathy of Alzheimer’s type is primary and, moreover, possibly congenital in AD development.
Abstract
Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system that is characterized by recurrent bouts of acute neuroinflammation and chronic neurodegeneration. Treatments for MS are aimed at prevention of disability in the future or restoring function in the present. Prevention treatments disrupt the underlying disease pathology, whereas restorative treatments address not only the disease’s primary effects on the central nervous system, but also secondary effects on other parts of the body and tertiary effects on each patient’s psychosocial functioning. MS symptoms can have primary, secondary, and tertiary components, which can interlock and reinforce each other. Restorative treatment should tease apart these components and address them separately. In this article on symptom management, we focus on treatments that aim to maximize each component of function.
Charles M. Lepkowsky, Ph.D.
Independent Practice, 1143 Deer Trail Lane, Solvang, CA 93463-9519
Abstract
Alzheimer’s disease is the most common form of dementia affecting older adults. Alzheimer’s disease also shares a significant association with Major Depressive Disorder. Glutamatergic excitotoxicity via NMDA receptors is believed to be a key mechanism underlying neurodegeneration in Alzheimer’s Disease. Blockade of NMDA receptors by NMDA antagonists like Memantine appears to inhibit glutamatergic excitotoxicity. Memantine also increases dopaminergic activation through agonism of sigma-1 receptors. The combination of these two mechanisms is believed to underlie Memantine’s improvements in memory, cognition and general functioning in AD patients. Auvelity was recently approved by the FDA for the treatment of Major Depressive Disorder in adults. Auvelity’s relevant mechanism of action is a combination of its blockade of NMDA receptors with consequent antagonism of the glutamatergic neurotransmitter pathway, and its agonism of the sigma-1 receptor. Because Auvelity and AD medications like Memantine employ the same mechanism of action, it is hypothesized that Auvelity might be a potential medical treatment for reducing the symptoms of Alzheimer’s disease.
