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Neurodegeneration and brain disorders

  • As 2019 comes to an end, it is important to mention that this year has seen a lot of progress as regards mental health. The increased awareness among Nigerians is noteworthy. Topics such as depression and Post Traumatic Stress Disorders are being discussed loudly and boldly, and this has in so many ways helped reduce the culture of silence and shame that is often attached to these diseases. It has also contributed to boosting our confidence in the fact that we can take control of our mental health. However, before we do that, we must attempt to understand what is wrong with us.

    There are many different diseases that can affect our mental health. More prominent in the aged, neurodegenerative diseases are an example. These diseases specifically target the brain cells causing them to degenerate. Their degeneration may result in their death and brain cells are so slow to regenerate. Neurodegenerative diseases continue to pose a threat to the quality of life especially among the elderly. The most common of them is Alzheimer’s disease which causes periodic memory loss thereby affecting mental functioning and physical activity. Alzheimer’s disease affects millions of Nigerians as about 1.5 million cases are reported yearly. Though largely terminal, learning about neurodegenerative diseases may help to improve quality of life.

    What are neurodegenerative diseases?

    Neurodegenerative diseases are diseases that cause the breaking down of parts of the brain resulting in progressive debilitation of the brain activity caused by micro communications between the brain cells. (Berman A et al. 2018). 

    Neurodegenerative diseases are some of the most deeply studied diseases for decades and that have produced slow results mostly because they require intricate study of the diseases and because of this, they are a major cause of death and remain a threat to health. Some of these diseases include Alzheimer’s disease, Parkinson’s disease, dementia, Huntington’s disease amongst others. The diseases are more prevalent in the aged, and this has been studied to be perhaps due to the prolonged lifespan that is nowadays common. Evidence from research suggests that genetic, cellular and circuit dys-regulation results can lead to cellular and cognitive hallmarks of some neurodegenerative diseases such as Alzheimer’s disease while Parkinson’s disease is characterized by progressive death of dopamine neurons. Amyotrophic Lateral Sclerosis (ALS) is a progressive degeneration of motor neurons in the brain and spinal cord. (Geodert M, 2016)

    Lee (2006) suggest that misfolded proteins which are often associated with several pathological disorders such as cystic fibrosis and Gaucher’s disease are also related to neurodegenerative diseases including the primary cause of Alzheimer’s, Parkinson's and Huntington’s diseases. Misfolded protein which is an imbalance in protein concentration can be as a result of mutations in genes encoding disease-associated proteins. But more general causes of misfolding or abnormally folded proteins remain unknown.

    According to (Geodert M., 2001), a study of the rare forms of Alzheimer’s diseases, frontotemporal dementia and Parkinson’s disease led to the identification of gene defects that cause the inherited variants of the different diseases. The defective genes in most cases have been found to encode or increase the expression of the main components of the micropathologicallesions. Therefore it can be established that the basis of the familial forms of these diseases is a toxic property conferred by mutations in the proteins that make up the filamentous lesions.

    Concepts of neurodegenerative diseases began to develop over a century ago when the German school of neuro-pathologists described the salient histological features of the most common neurodegenerative disease - Alzheimer’s disease. Alois Alzheimer after whom the disease was named discovered the neurotic plaques and neurofibrillary lesions in Alzheimer’s disease.

    Types of neurodegenerative diseases

    Neurodegenerative diseases are caused by several factors that result in the brain’s debilitation. According to their symptoms, several types of neurodegenerative diseases have been discovered. These are;

    1. Alzheimer’s disease
    2. Parkinson’s disease
    3. Spinal muscular atrophy
    4. Prion’s disease
    5. Huntington’s disease
    6. Motor neurone disease
    7. Spinocerebral ataxia

    Alzheimer’s disease

    Selkoe (2002) describes Alzheimer’s disease as a late on-set dementing illness with a progressive loss of memory, performance, speech and recognition of people and objects. There is a degeneration of neurons particularly in the basal forebrain and hippocampus, but at least as important for pathogenesis may be synaptic pathology and altered neuronal connections. The disease is the most common cause of dementia worldwide.

    Alois Alzheimer was a German neuroanatomist and clinical psychiatrist. On the 3rd of November, 1906, he reported a particularly severe disease process of the cerebral cortex to the 37th meeting of South-west German scientists in Tubingen where he described a woman whom he had followed from her admission for paranoia, progressive sleep and memory disturbance and confusion until her death five years later. His report noted distinctive plaques and neurofibrillay tangles on the brain histology. This discovery attracted little interest except from Kraeplin who promptly included Alzheimer’s disease in the third edition of his text, Psychiatrie in 1910.

    Alois Alzheimer went further to publish three other cases in 1909 and a plaque only variant in 1911 which later showed to be a different stage of the same process after re-examination in 1993.

    Alzheimer examined and investigated the first patient’s brain after her death on 8th April 1906 both morphologically and histologically. The results formed the basis for Alzheimer’s lecture at the Tubingen meeting (Hippius Hanns, 2003).

    Stages

    There are seven stages of Alzheimer’s disease and they are;

    Stage 1: Whereby the disease is not detectable dementia is not noticeable

    Stage 2: A very mild decline in memory problems

    Stage 3: Mild decline

    Stage 4: Moderate decline

    Stage 5: Moderately severe decline

    Stage 6: Severe decline

    Stage 7: Very severe decline

    Causes

    Research has shown that Alzheimer’s disease starts before its symptoms are seen. The exact cause of the disease is not clear, but people with Alzheimer’s have defective acetylcholine both in concentration and in function. Acetylcholine is a major neurotransmitter in the brain. Acetylcholine causes muscles to contract, thereby activating it. In that way, it plays an important role in short-term memory and learning. Alzheimer’s disease is said to be caused by a combination of genetic, lifestyle and environmental factors that affect the brain over time. It is caused by specific genetic changes that may cause the development of the disease. The damage of Alzheimer starts in the region of the brain that controls memory. The loss of neurons spreads in a somewhat predictable pattern to other regions of the brains. It causes the shrinking of the brain. By the late stage of the disease, the brain has shrunk significantly. There are two proteins that researchers are focused on;

    1. Plaques: Plaques are fragments clustered together from beta-amyloid, which is a leftover fragment of a larger protein. These clusters are said to have a toxic effect on neurons and to disrupt cell-to-cell communication. These clusters form larger deposits called amyloid plaques.
    2. Tangles: in Alzheimer’s disease, tau protein collapses into aggregates called tangles. When this happens, the microtubules can no longer sustain the transport of nutrients and other essential substances in the nerve cells, which eventually leads to death. This is different from in healthy brain where the tau protein helps the microtubules remain straight and strong.

    Mechanism of action of Alzheimer's disease  

    Memory functions in the brain are mediated primarily by the hippocampus; this includes associated structures such as dentate gyrus, subiculum, parasubiculum, presubiculum and entorhinal cortex. (Walsh DM, 2004).

    Accelerated hippocampal atrophy that is especially marked in the frontotemporal horn and atrophy of the cerebral cortex is associated with Alzheimer’s disease. Early phase neurocognitive symptoms of Alzheimer’s include memory and spatial learning deficits which are both associated with the hippocampus. (Alves L, 2012).

    Alzheimer’s disease results in a significant atrophy o the entorhinal cortex, further evaluation reveals neuronal degenerations and the presence of neurofibrillary tangles.

    The characteristic features of Alzheimer’s disease, AD, are the appearance of extracellular amyloid beta (AB) plaques and neurofibrillary tangles in the intracellular environment, neuronal death and the loss of the synapse. All of which contribute to progressive cognitive decline.

    Defective memory in the early stages of the disease is associated with changes in the hippocampus and the entorhinal cortex. As many as 80% of neurons in the hippocampus die over the course of the disease. This neuronal loss damages the performant pathway of the entorhinal cortex between the hippocampus such that it creates an inhibition of efferent connections from the hippocampus and the cortex due to progressive degeneration of neurons. (Walsh DM, 2004).

    Different cell types are affected by AD. They include; locus ceruleus, the nuclei of the brain stem (e.g. raphe nucleus), reticular formation, amydala, substantia nigra, striatum, hypothalamus, thalamus, claustrum and select regions of the cerebral cortex.

    In transgenic mouse models of AD, amyloid plaques occur in the vicinity of structural changes capable of altering brain function including neurite dystrophy and spine loss. (Tasai J, 2004).

    Synaptic loss is likely caused by a morphological reflection of the synaptic dysfunction that begins early in the disease. This strongly correlates with cognitive deficits in Alzheimer’s disease.

    Therefore the progressive atrophy of dendritic spines is proportional to AD pathogenesis and can be used as an indicator of advancing disease. This is seen and has been tested in post-mortem brain tissues where AD patients exhibited a reduced number of dendritic spines and reduced synapse density in the hippocampus and cortex relative to age-matched control brain tissues. A direct correlation between dendritic spine loss and worsening mental status was thus recorded.

    The action of glutamine in AD cannot be ignored. As the principal excitatory neurotransmitter in the Central Nervous System, it mediates neuronal plasticity, neural transmission, memory process and learning. (Kochan S, 2013).

    TAU Protein

    Tau proteins are highly soluble microtubule-associated protein tau (MAPT). They are found majorly in neurons. One of their main functions is to modulate the stability of axonal microtubules. When the activity of enzymes that act on tau called taukinases are increased, tau proteins build-up causing the tau proteins to misfold and clump, forming micro-fibrillary tangles. In patients with AD, hyperphosphorylation causes the proteins to dissociate from the microtubules, disturbing the transport structure and resulting in starvation of neurons and ultimately, cell death.

    Treatment of Alzheimer’s disease

    There is no known cure for AD. However, drugs and medications are available to help with memory and cognitive problems. They are;

    1. Memantine (Nemada); this drug works by slowing the progression of symptoms of moderate to severe AD, It can be used sometimes in combination with a cholinesterase inhibitor. The side effects associated with this drug are rare. they are dizziness and confusion
    2. Cholinesterase Inhibitors: cholinesterase facilitates the lysis of choline-based esters which usually serve as neurotransmitters. Cholinesterase inhibitors inhibit the production of these choline-based esters and boost cell-to-cell communication by preserving a chemical messenger that is depleted in the brain by AD. The drug may also help to improve neuropsychiatric symptoms such as agitation or depression. Some of these drugs include; donepezil, galantamine and rivastigmine. Side effects include nausea, diarrhoea, and loss of appetite, sleep disturbance and even cardiac arrhythmia in people with cardiac conditions.

    A recent discovery in drug development

    In October 2019, a developmental drug was submitted to the US Food and Drug Administration by Biogen Inc., a US-based pharmaceutical company. The drug targets the amyloid plaques in the brain believed to be an essential component of Alzheimer’s disease. (Dogan, 2017)

    Alzheimer’s disease is a terminal disease that involves the progressive degeneration of the brain over a specific period of time. The degeneration often follows a pattern that includes dementia. Amyloid, a protein that the body produces naturally, accumulates to form insoluble plaques. This is one of the hallmarks of the disease. As the disease progresses, the brain shrinks. In the early stages of the disease, short-term memory declines due to degeneration of the cells in the hippocampus. As it progresses towards the final stage, cognitive impairment worsens. Constant care is needed for people with Alzheimer’s disease for a better, comfortable life. Averagely, sufferers may live for about 10 years, but this is not definite as some patients live for up to 20 years.

    References

    A, B. T. (2018). What are Neurodegenerative Disease and How Do They Affect the Brain? Front. Young Minds. , 70.

    Alves L, C. A. (2012). Alzheimer's disease: a clinical practice-oriented review. Front. Neurol, 63.

    Danysz W, P. C. (2012). Alzheimer's disease. Beta amyloid glutamate, NMDA receptors and memantine . Br. J. Pharmacol., 324-352.

    Dogan, S. K. (2017). Mechanisms of Alzheimer's Disease Pathogenesis and Prevention: the brain, neural pathology, N-methyl-D-Aspartate Receptors, Tau proteins and other risk factors. Clinical pharmacology and neuroscience, 1-8.

    Hippius Hanns, G. N. (2003, March). The discovery of Alzheimer's disease. Dialogues Clin Neurosci, 101-108.

    J., S. D. (2002). Alzheimer's disease is a synaptic failure. Science 298, 789-791.

    Jason Weller, A. B. (2018). Current Understanding of Alzheimer's disease diagnosis and treatment. Faculty Rev, 101-108.

    Kochan S, A. K. (2013). Effects of NMDA receptors blockade during the early development period on the retest performance of Adult Wistar rats in the elevated plus maze. . Neurochem Res., 1496-1500.

    M., G. (2001). Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci, 492-501.

    Tasai J, G. J. (2004). Fibrillar leakages of neuronal branchesmyloid deposition leads to local synaptic abnormalities and br. Nat. Neurosci., 1181-1183.

    Walsh DM, S. D. (2004). deciphering the molecular basis of memory failure in Alzheimer's disease. Neuron, 181-193.

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