Frontiers in Clinical Drug Research - Alzheimer Disorders

Alzheimer’s disease (AD) is a neurodegenerative disorder of the brain, inducing progressive severe presenile and senile cognitive decline, resulting in vegetative stage eventually. From the etiological point of view the main causative factor, remains unknown, in spite of the steady augmentation of the research efforts. Golgi staining revealed the substantial alterations of the dendritic branches and the tremendous loss of spines even in the initial stages of the disease. Electron microscopy reveals morphological changes of the mitochondria in neurons and astrocytes associated with fragmentation of cisternae of Golgi complex and pathological alteration of the dendritic spines, even in areas of the brain, which demonstrate minimal tau pathology and few amyloid β deposits. It is attempted to describe the ultrastructural alterations of the cerebellar cortex in early cases of AD, focusing the study mostly on mitochondria, Golgi apparatus, dendritic branches, dendritic spines and synapses in the cerebellar hemispheres and the vermis. Mitochondria demonstrated an impressive polymorphism in the soma, the axonal and dendritic profiles of Purkinje cells, the climbing fibers, the mossy fibers and the synapses. Electron microscopy revealed also marked fragmentation of cisternae of Golgi complex in large number of Purkinje cells, granule and stellate cells in the vermis and the cerebellar hemispheres. The fragmentation of the Golgi complex and the poverty in vesicles in cis- and trans-Golgi network in the soma of Purkinje cells in Alzheimer’s brains coincide with the synaptic loss, the shortage of the dendritic arborization and the pathological alterations of the spines. Numerous spines included large multivesicular bodies, altered spine apparatus, and unusual mitochondria. Giant elongated spines were seen in a substantial number of Purkinje cells. In many presynaptic terminals of parallel and mossy fibers, electron microscopy revealed a dramatic loss of the synaptic vesicles associated with marked polymorphism. On the basis of the mitochondrial and Golgi complex pathology, new therapeutic strategies protecting those organelles might be proposed for the treatment of early cases of AD.

This chapter reviews the major pathological features and hypotheses in Alzheimer’s disease (AD). Hypothesis-based and mechanism-based strategies of clinical drug research and development for AD therapy and prevention are discussed. The current available drugs and their applications are described. In addition, the potential drugs in trials and under advanced stage of development are introduced.

AD displays 3 typical pathologies: loss of cholinergic neurons in the basal ganglia of forebrain, β-amyloid (Aβ) plague deposition and neurofibrillary tangles (NFTs) of tau protein. Aβ oliogmers and highly phosphorylated tau protein are generally considered to be critical factors for the pathogenesis of AD. AD is also aggravated by distress.

Primary and experimental drugs for AD based on these hypotheses are generally classified as follows: cholinergic drugs, antipsychotic drugs, Aβ and tau related drugs, neuroprotective drugs, others with atypical hypothesized mechanisms of action. As for patients, the drugs could be divided into drugs approved and drugs under clinical trials, while the approved ones include drugs to treat AD and drugs to treat AD associated symptoms.

As to the application of AD drugs, the most commonly prescribed drugs are classified as cholinesterase inhibitors. Memantine, antagonist of the NMDA receptor, is the second class of AD medicine that is approved for treatment of moderate to severe AD. Antidepressant, anxiolytics and antipsychotics are used to treat AD associated symptoms. Besides, antioxidant, statins, Non-steroidal anti-inflammatory drugs (NSAIDs) are those that belong to the family of “old drugs with new actions”. Nonprescription medications, like vitamin C and vitamin E, curcumin and ginko are probably advised to prevent AD. Another effort has been made towards metabolically non-reversible dimeric or hybrid compounds with multiple mechanisms of action.

The promising drugs loom in clinical trials since new strategies have been adopted to address the etiology of AD, i.e. Aβ, NFTs and neuronal loss. The tau related drugs include GSK-3β inhibitors, protein phosphatase 2A (PP2A) activators, paired helical filaments (PHF) antibody, and methylene blue with unknown mechanisms. Aβ related drugs include β-site APP-cleaving enzyme (BACE) inhibitors, γ-secretase inhibitors, γ- secretase modulators, active and passive Aβ vaccination drugs, and human intravenous immunoglobulin (IVIG). The neuroprotective drugs are those that would maintain the homeostasis of microenvironment, including anti-inflammatory, anti-oxyidant, metal chelators, statins and neurotrophic agents.

In conclusion, the patients would be prescribed tacrine, donepezil, rivastigmine, galantamine or memantine to treat mild or moderate to severe AD respectively. In the meantime, they would have taken antidepressants, anxiolytics and antipsychotics to deal with AD associated symptoms. Besides those approved, the effort to develop new drugs to cure AD never stops. The potential drugs are on their promising way through clinical trials. Albeit the failures and setbacks, AD scientists and clinicians are feverishly researching to deliver an effective therapy for the many patients.

Volumetric measurement of the Hippocampus is currently a growing and an upcoming area for a number of neuropsychiatric disorders. In the recent years, volumetric analysis of hippocampus in Alzheimer’s disease has received lot of attention due to close association of this structure in pathophysiology of this devastating disease. In the coming times, it may even be included as a formal part of clinical evaluation of dementia. However, as an evolving technique it has some issues, limitations and areas where agreement has not been achieved. Though now it is increasingly being practiced and accepted - there are some issues that need attention of researchers in this field. Some of the issues are: radiological definition i.e. what should be considered as Hippocampus and how much area is to be included for manual volumetry. Also, the development of population norms for a normative data for voxel based morphometry remains a challenge. Present chapter reviews these methods and issues.

The clinical hallmarks of Alzheimer’s disease (AD) are cognitive and memory deterioration with progressive deficit in retrieval of memory. As the disease progresses neurodegeneration continues in the brain worsening the symptoms. Eventually, this leads to dementia - the most common dementia of the elderly. The upstream etiology of this disease is multi-factorial, and intimately related to the downstream development of neurofibrillary tangles, amyloid plaques, and cerebral amyloid angiopathy. Currently we have no strategies/therapies to prevent these pathologies, or otherwise retard or halt the relentless progression of AD. Chronic subclinical inflammation has been documented to be an essential risk factor that underpins aging, AD, and other age-related conditions. Chronic systemic inflammation, with lowgrade and unresolved features, is known to be an underlying feature also in depression, and obesity. Persistent chronic up-regulation of pro-inflammatory mediators e.g., TNF- α, IL-1β, IL-6, and other cytokines during systemic inflammation and endotoxemia upregulate redox imbalance-ROS signaling pathways, and enhance proinflammatory and NF-κB signaling in the brain. Further, “systemic inflammation to neuroinflammation” may serve as a bridge between ongoing innate immune activation and neurocognitive dysfunction in aging. The above key proinflammatory molecular elements are also associated with APOE4-positive elderly, infection, and alcohol abuse. Indeed, infections in the elderly are very common, and ethanol is the single most abused drug worldwide. These are, therefore, synergistic pathophysiological factors that may underlie the onset and progression of cognitive dysfunction.

Alzheimer Disease (AD) is the most common form of dementia in the world and is a cause of infirmity in the older people. The prevalence of this disorder increases exponentially with age ranging from approximately 2% at the age of 60-65 years to more than 30%-35% in people older than 80 years.

AD pathological modifications begin to accumulate for years, before all typical (emotional, physical, or cognitive) symptoms emerge. The classical hallmarks of AD are senile plaques and neurofibrillary tangles, which consist of amyloid-β (A) and hyper-phosphorylated tau proteins. The exact aetiology of this pathology is still unclear, and it is considered a complex multifactorial disorder in which genetics, epigenetics and environmental factors contribute to prompt neurons towards a premature death.

For the last 20 years, the “amyloid cascade hypothesis” has dominated research aimed at understanding, preventing and curing the AD. Several strategies have been studied for setting up therapies against amyloid deposits, which have been successful in curing the disease in some animal models, but they have never been effective in human AD patients. These failures have supported the hypothesis that the up-regulation of amyloid precursor protein (APP) and Aβ could be necessary to respond to inflammation/oxidative stress-associated neurodegeneration. In particular the oxidative stress associated to the increase of free radicals have been demonstrated to be involved in the etiopathogenesis of AD and enhanced levels of oxidative injuries markers in cellular macromolecule (lipids, DNA, proteins) have been found in the central nervous system and peripheral tissues of AD patients. These findings demonstrate that reactive oxygen species (ROS) targeted therapy can be successful in AD treatment.

Epigenetics refers to all meiotically and mitotically reversible heritable changes in gene expression which occur independently of DNA sequence, and are principally due to changes in DNA methylation, chromatin structure and microRNA (miRNA) expression. Emerging evidences from animal and human studies suggest that epigenetic mechanisms are involved in learning and memory, and that many of biological pathways dysregulated in AD are controlled through epigenetic modifications. This rapidly expanding field of neuroepigenetics seems to be particularly promising in identifying new aspects and, above all, new therapeutic strategies for treating this disorder. The approval of epigenetic drugs for the treatment of other diseases (like cancer) opens the door for the development of similar drugs also for AD.