Overview

The underlying pathophysiology of all neurodegenerative diseases is the dysfunction and ultimate death of neurons. Neurodegenerative diseases are progressive in nature with a worsening of clinical symptoms over time. The neuronal loss in different neurodegenerative diseases is asynchronous with symptoms progressing as a result of a cumulative loss of the neurons that synthesize the neurotransmitters essential to signal propagation through the particular brain circuitry associated with a given disease. Different disease phenotypes occur with neuron loss depending on the neuronal population affected, the insult initiating the cell death cascade, and the genetic makeup of the individual. For example, memory or coordinated movement is not the function of a single specific neuronal population or brain region but involves several, such that the loss of one key element can perturb neurotransmitter homeostasis (excitatory versus inhibitory), thus affecting the final integrated output of the system.

Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS) are the best known neurodegenerative diseases, but also included in the category of neurodegeneration are demyelinating diseases (e.g., multiple sclerosis, Charcot-Marie-Tooth, neuromyelitis optica), neuropathies (e.g., diabetic, human immunodeficiency virus (HIV), chemotoxic), Down's syndrome, prion diseases (e.g., CreutzfeldtJakob disease), tauopathies (e.g., Pick's disease, frontal temporal dementia with parkinsonism (FTDP)), additional trinucleotide repeat or polyglutamine (polyQ) diseases (e.g., spinocerebellar ataxias, dentatorubral-pallidolysian atrophy, Freidreich's ataxia), multiple systems atrophy, stroke, and traumatic brain injury. The current chapter focuses on AD, PD, HD, and ALS: multiple sclerosis and stroke are covered elsewhere in this volume (see 6.09 Neuromuscular/ Autoimmune; 6.10 Stroke/Traumatic Brain and Spinal Cord Injuries).

AD affects cognitive function at its onset, while in PD, HD, and ALS, motor function is initially impaired. In the later stages of PD and HD, and within a specific variant of ALS, progressive cognitive dysfunction and dementia may occur.

Neurodegenerative diseases can be classified into two predominant types based upon their nature of inheritance. If there is no definable pattern of inheritance, the neurodegenerative disease is referred to as idiopathic or sporadic, whereas diseases with a definable inheritance pattern and genetic linkage are referred to as familial. The two categories may represent different entities. AD, PD, and ALS exist in both idiopathic and familial disease forms while HD is a familial disease, with 100% penetration with inheritance of the identified gene. A number of genetic risk factors (susceptibility genes) as well as putative environmental exposure factors (epigenetics) are associated with the development of idiopathic forms of AD, PD, and ALS. Thus, as with other disease states, genetics and environment (nature and nurture) play key roles in the development of neurodegenerative diseases. Since multiple genetic risk factors are associated with central nervous system (CNS) degenerative diseases, it is anticipated that treatment will need to be prophylactic, based on individual genetic profiles. However, this will require the development of drugs with relatively benign safety profiles to allow for long-term treatment and biomarkers to diagnose the disease and to assess disease progression and drug responses.

In each neurodegenerative disease, there is selective neuronal vulnerability such that the primary neuronal population affected differs. Common factors that are potential mediators of the disease process include: increased oxidative burden (reactive oxygen species); impaired energy metabolism; lysosomal dysfunction; protein aggregation/ inclusion-body formation; inflammation; excitoxicity; necrosis; and/or apoptosis. Since many of these features underlie multiple CNS disease states, new chemical entities (NCEs) targeting these mechanisms may have general utility. As evidence of this, evaluation of antioxidants, antiinflammatory agents, glutamate receptor antagonists, and antiapoptotic agents for effects on neuronal survival has been conducted in animal models of neurodegeneration with some having been clinically evaluated in multiple neurodegenerative disease states (e.g., minocycline, riluzole).

Drugs approved over the last 10-15 years for the treatment of neurodegenerative diseases, mainly cholinesterase inhibitors, have provided modest symptomatic improvement. However, evidence is emerging that some of these drugs may alter the course of disease (e.g., dopamine (DA) agonists for treatment of PD). In contrast, the cholinesterase inhibitors approved for AD have modest efficacy.

Current research is focused on finding NCEs to halt disease progression - the 'holy grail' for neurodegenerative disease. However, in the absence of a clear understanding of the mechanism(s) causing cell death, this research is almost exclusively dependent on identifying potent, selective, and drug-like NCEs, active at molecular targets thought to underlie the process of neurodegeneration, to build confidence for these targets and derive proof of concept. The theoretical effects of symptomatic treatment versus neuroprotective treatment on disease progression are shown in Figure 1. Basically, with symptomatic treatment, a relatively immediate improvement in functional response occurs but on withdrawal the natural rate of disease progression resumes. Neuroprotectants are anticipated to alter the rate (e.g., change the slope) of disease progression but not necessarily improve functional responses in the short term. This is an important issue in that many of the animal models used to evaluate NCEs have been developed using short-term measures, e.g., Morris water maze.

Figure 1 Time course of Alzheimer's disease (AD) progression. The solid line indicates normal disease progression - functional capability of the AD patient decreases in a linear manner with time. Symptomatic treatment, e.g., cholinesterase inhibitors, can produce an acute stabilization of the disease, resulting in a time shift in disease progression. It is debatable whether the acute stabilization is a drug-related or placebo effect. A neuroprotective agent, none of which has yet progressed to proof of concept in humans, is shown in the figure as markedly delaying disease progression such that normal aging may precede serious cognitive decline. An 'ideal' neuroprotective agent may even reverse disease progression, resulting in a progression, line approaching the horizontal.

Figure 1 Time course of Alzheimer's disease (AD) progression. The solid line indicates normal disease progression - functional capability of the AD patient decreases in a linear manner with time. Symptomatic treatment, e.g., cholinesterase inhibitors, can produce an acute stabilization of the disease, resulting in a time shift in disease progression. It is debatable whether the acute stabilization is a drug-related or placebo effect. A neuroprotective agent, none of which has yet progressed to proof of concept in humans, is shown in the figure as markedly delaying disease progression such that normal aging may precede serious cognitive decline. An 'ideal' neuroprotective agent may even reverse disease progression, resulting in a progression, line approaching the horizontal.

As the average human lifespan has increased, a concomitant increase in the incidence of deaths attributed to neurodegenerative disease has occurred.1 According to the National Vital Statistics Report of the US Centers for Disease Control, life expectancy from birth in 2003 was 77.6 years.1 This represents a 0.3-year increase from 2002, which was partially driven by increases in the number of deaths listed as due to AD, the eighth leading cause, and PD, the 14th leading cause. In comparison, the average life expectancy in 1900 was 47.3 years. Thus, with time, the pharmacoeconomic impact of neurodegenerative diseases on society is increasing. At the same time, new drug approvals have decreased, especially in the CNS area, suggesting that as technology has advanced, productivity has fallen. An interesting debate is ongoing that cancer may represent a risk factor in dementia,2 reflecting the yin and yang of cell death therapeutics. In cancer, the task is to enhance cell death, while in neurodegeneration the converse is true.

New technologies in genetics (transgenic or gene-null vertebrates and invertebrates) have been used as novel preclinical models of disease and for testing NCEs. For neurodegenerative diseases, rodent, fly (Drosophilia), and worm (Caenorhabditis elegans) models exist for familial forms of AD, PD, HD, and ALS.3 Clinical back-validation of these models has been limited since, for most of these engineered models, the human disease process is not fully recapitulated. However, invertebrate models provide facile systems for cost-effective screening of NCEs for their effects on the basic biological process that may underlie disease pathophysiology. Genetically engineered nonhuman primate models are also being developed, although the availability of animals and costs will limit general applicability and widespread utility.

A major discourse in drug discovery as productivity has decreased is that the 'low-hanging fruit' has been harvested. In the area of neurodegeneration, the drugs launched over the past two decades target the same mechanism, e.g., cholinesterase inhibitors for AD and DA agonists for PD. While improvements in pharmacokinetics or reduced side effect liabilities have been made in second-generation compounds and have aided treatment management, these have had limited impact in advancing the understanding of disease causality. Additionally, a number of promising compounds acting at newer targets based on elegant preclinical hypotheses have singularly failed in the clinic, e.g., estrogen and anti-inflammatory agents in AD.

Conceptually, drug therapies for neurodegenerative disease can be divided into three treatment categories: (1) symptomatic; (2) protective; and (3) curative. Strategies for symptomatic and protective treatments will be discussed in this chapter. Curative treatment, yet to be achieved, is typically envisaged in terms of tissue (stem cell) transplantation and gene replacement strategies that are beyond the scope of this chapter.

Unraveling Alzheimers Disease

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