New Developments in Research Related to Protective Therapies and Treatments for Alzheimers Disease - Essay Example

Alzheimer’s Disease Introduction Alzheimer’s Disease is a “progressive and irreversible brain disorder that is manifested in dementia, motor lesions, and behavioral deficits” (Welsh, 2006, p.88). In the United States, Alzheimer’s Disease affects nearly a tenth of the population above 65 years of age; hence it is a growing concern in health care. Alzheimer’s Disease is diagnosed on the basis of histopathological evidence at brain autopsy or biopsy. Two characteristic lesions are evidence of the disease. They include senile plaques, extracellular deposits of amyloid β  (Aβ) peptides; and neurofibrillary tangles which are “intracellular aggregates of the microtubule associated protein tau” (Sun, 2007, p.40). The relationship of neuropathological features of Alzheimer’s Disease to the emergence of cognitive deficits, is not fully understood currently. However, “the process that results in the accumulation of  Aβ as amyloid triggers the complex pathological changes ultimately leading to cognitive impairments” (Sun, 2007, p.40), known as the ‘amyloid cascade’ hypothesis. Lichtien and Mohajeri (2008) state that the high morbidity, socioeconomic costs, and lack of specific treatments indicate the importance of research on Alzheimer’s Disease. Thesis Statement: The purpose of this paper is to investigate new developments in research related to protective therapies and treatments for Alzheimer’s Disease. Alzheimer’s Disease Research: Antibody-Based Approach to Protection Evidence from Lichtien and Mohajeri’s (2008) research on the efficacy of anti-amyloid immunization strategies, indicates that they serve as effective protective mechanisms against Alzheimer’s Disease. However, the underlying mechanisms of action of therapeutic antibodies, particularly their impact on the complex amyloid β peptide (Aβ) metabolism and various Aβ equilibria present both on the internal and external sides of the central nervous system, are not fully clear as yet. Moreover, physiological Aβ metabolism is not fully understood because of inadequate analytical tools to characterize and quantify treatment effects. Further, biomedical research is aimed at developing predictable therapies minimizing the risk of adverse effects such as brain inflammation and/ or hemorrhage caused by anti- Aβ immunization protocols. The researchers found that standard Enzyme Linked Immune Sorbant Assay (ELISA) protocols are inadequate in rational drug design, and there is a requirement for more complex analytical tools to be developed and applied. Tests ensuring greater reliability in the assessments of Aβ in free versus protein-bound form, as well as monomeric versus aggregated Aβ, will be key to identifying the mechanisms forming the basis for efficacy and safety of the different antibodies; these are at present in preclinical and clinical development for protection from Alzheimer’s Disease (Lichtien & Mohajeri, 2008). Research Findings on Treatment Methods for Alzheimer’s Disease Alzheimer’s Disease “is characterized by functional impairment in the neural circuits serving cognitive and memory functions” (Schouenborg, Garwicz, & Danielsen, 2011, p.89). This occurs mainly in the hippocampus or entorhinal cortical complex where the neurodegenerative burden of the disease is highest. Recent research reveals that effective treatment options for Alzheimer’s Disease include stem cell procedure, gene therapy, and deep brain stimulation. Stem Cell Procedure Cell replacement for functional brain repair is a complex area. Each neurodegenerative disease may require a case-specific approach to effectively rescue or replace particular types of neurons and neuronal networks. For example, stem cells may be required to differentiate into supporting cells, or may be genetically modified to release sufficient and appropriate trophic factors for the degenerating cells. On the other hand, stem cells may be directed to differentiate into neurons of a particular phenotype to release the neurotransmitter needed for a given neurodegenerative disorder such as Alzheimer’s or Parkinson’s. Thus, stem cell therapy could aim to promote cholinergic and dopaminergic cell survival and neurotransmission for Alzheimer’s Disease (Shihabuddin & Aubert, 2010). Stem cell therapy provides the advantage of being conducive to genetic engineering that can be used to control the timely release of trophic factors and neurotransmitters. Currently, the delivery of stem cells across the blood-brain barrier involves invasive surgeries with their associated risks. Non-invasive techniques for delivering therapeutic molecules, genes and cells are under intensive investigation. Intranasal delivery of therapeutic molecules is being explored, especially for the delivery of trophic factors for Alzheimer’s disease. Other techniques include focused ultrasound in the presence of microbubbles and guided by magnetic resonance imaging to reversibly and locally increase the permeability of the blood-brain barrier, and biomaterials helping therapeutics cross the blood-brain barrrier. This helps to deliver stem cells in a safe and less invasive manner than current intracranial transplantation (Hynenen, 2008). Gene Therapy Evidence from research has established that Nerve Growth Factor (NGF) prevents neuronal death or age-related atrophy in the adult brain. In Alzheimer’s disease (AD), cholinergic neurons in the basal forebrain die due to atrophy. This process forms the basis for attention deficit and overall cognitive decline in AD. Appropriately controlled clinical trials conducted carefully and obectively are required, to determine the ultimate usefulness of growth-factor gene delivery for neurological diseases. Additionally, improvements need to be made in the design and safety of gene-therapy vectors, to contribute to the advancement of gene therapy-based techniques. One of the limitations of this approach is that the amount of gene product delivered cannot be controlled. To improve the safety aspect of gene therapy, it is important to develop vector systems in which the expression of a gene can be regulated, and turned off if necessary. A promising new vector system with a tetracycline-sensitive element incorporated into its structure can be used to eliminate the biological effects of ex vivo NGF gene therapy in animals (Tuszynski, 2002). The extent and duration of therapeutic gene expression is another issue that impacts the potential efficacy of gene therapy. Earlier, many of the therapeutic genes used in these studies were expressed for a few weeks or less, thus limiting their efficacy. However, more recent vectors are capable of maintaining gene expression in vivo for months, and even years. “These improvements are a result of the use of novel promoters, expression enhancers, and post-transcriptional stabilisers of mRNA” (Tuszynski, 2002, p.56). Additionally, modern vectors induce only a negligible inflammatory response. Thus, sustainable gene expression is possible with the new generation of adeno-associated virus, lentivirus, and ‘gutless’ adenovirus vectors. Deep Brain Stimulation Laxton, Tang-Wai, McAndrews, et al (2010) hypothesized that fornix/ hypothalamus deep brain stimulation (DBS) may modulate neurophysiological activity in these pathological circuits, and possibly lead to clinical benefits. The researchers conducted a phase I trial in 6 patients with mild Alzheimer’s Disease under medical treatment. The patients received continuous stimulation for 12 months. Deep brain stimulation encouraged “neural activity in the memory circuit, including the entorhinal and hippocampal areas, and activated the brain’s default mode network” (Lang, Tang-Wai, McAndrews, et al, 2010, p.521). Positron Emission Tomography (PET) scans indicated an early and marked reversal of the impaired glucose utilization in the temporal and parietal lobes that continued to be upheld after 12 months of continuous stimulation. Measurements from the Alzheimer’s Disease Assessment Scale cognitive subscale and the Mini Mental State Examination showed possible improvements and/ or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse effects. The authors concluded that there is a severe need for novel therapeutic approaches for Alzheimers’ Disease. The pathologial brain activity in this condition should be modulated with deep brain stimulation, and needs further research studies. Tierney, Sankar, and Lozano (2011) assert that modulation of motor activity within motor, mood, and cognitive circuits has beneficial outcomes for Alzheimers’ Disease, Parkinson’s Disease, and treatment-resistant depression. It is possible that applications for deep brain stimulation will continue to expand as accumulating data establish its safety and efficacy profile. Conclusion This paper has highlighted new research developments related to protective therapies and treatment approaches for Alzheimers’ Disease. Protective drugs are currently being developed in preclinical and clinical settings. Mechanisms that are key to efficacy and safety of the different antibodies need to be identified through tests ensuring greater reliability in the assessments of Aβ in free versus protein-bound form, as well as monomeric versus aggregated Aβ. It is evident that stem cell procedure, gene therapy, and deep brain stimulation are have the greatest current and future potential among effective treatment methods for Alzheimers’ Disease. References Hynynen, K. (2008). Ultrasound for drug and gene delivery to the brain. Advanced Drug Delivery Reviews, 60, pp.1209-1217. Laxton, A.W., Tang-Wai, D.F., McAndrews, M.P., Zumsteg, D., Wennberg, R., Keren, R., Wherrett, J., et al. ‘A phase 1 trial of Deep Brain Stimulation of memory circuits in Alzheimer’s Disease’. (2010 October). Annals of Neurology, 68(4), pp.521-534. Lichtien, P. & Mohajeri, M.H. (2008). ‘Antibody-based approaches in Alzheimer’s research: Safety, pharmacokinetics, metabolism, and analytical tools’. Journal of Neurochemistry, 104(4), pp.859-874. Schouenborg, J., Garwicz, M., & Danielsen, N. (2011). Brain machine interfaces: Implications for science, clinical practice and society. The United States of America: Elsevier. Shihabuddin, L.S., & Aubert, I. (2010). Stem cell transplantation for neurometabolic and neurodegenerative diseases. Neuropharmacology, 58, pp.845-854. Tierney, T.S, Sankar, T., & Lozano, A.M. (2011). ‘Deep brain stimulation: Emerging indications’. Progressive Brain Research, 194, pp.83-95. Tuszynski, M.H. (2002 May). Growth-factor gene therapy for neurodegenerative disorders. The Lancet: Neurology, 1, pp.51-58. Welsh, E.M. (2006). New research on Alzheimer’s Disease. New York: Nova Publishers. Read More