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The Curse of our Control System

By Suchetana Ray Chaudhuri

Fighting Neurodegeneration by Understanding Inflammation ...

The brain is the organ of destiny. It holds within its humming mechanism, secrets that will determine the future of the human race.

– Wilder Penfield

The brain is an extremely complex organ with vast numbers of pathways that allow us to do the amazing things that we do. The brain is made up of billions of cells that we depend on every second of every day for proper functioning. Neurons communicate with each other to perform every function of the brain, whether it involves moving around, thinking about topics learned in school, talking to friends, or remembering the list of things we want to buy from the grocery store. Because of the brain’s complexity, brain disorders can arise from very small miscommunications between cells.

Neurology, in 1969, was focussed on diagnosis of the disease, primarily by physical examination. People going into neurology were always warned that it was a speciality in which one could diagnose, but not treat. Epilepsy, migraine and Parkinson’s Disease had the most effective therapies. Although examination of a living brain was difficult 40 years ago, pathological studies of post mortem human brains had been performed for decades. 

Etymologically, the word neurodegeneration is composed of the prefix neuro which designates nerve cells (neurons) and suffix degeneration which refers to, in the case of tissues and organs, a process of losing a structure or function. Thus, in the strict sense of the word, neurodegeneration corresponds to any pathological condition primarily affecting neurons. In practice, neurodegenerative diseases represent a large group of neurological disorders with heterogeneous clinical and pathological expressions affecting specific subsets of neurons in specific functional anatomic systems; they arise for unknown reasons and progress in a relentless manner.

Among the hundreds of different neurodegenerative disorders, so far, the lion’s share of attention has been given only to a handful, including Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and Amyotrophic lateral sclerosis (ALS).

The most consistent risk factor for developing a neurodegenerative disorder, especially AD or PD, is increasing age. Over the past century, the growth rate of the population aged 65 and beyond in industrialized countries has far exceeded that of the population as a whole. Thus, it can be anticipated that, over the next generations, the proportion of elderly citizens will double, and, with this, possibly the proportion of persons suffering from some kind of neurodegenerative disorder.  With few exceptions, the causes of neurodegenerative diseases are essentially unknown, and even when they have been identified, the mechanisms by which they initiate the disease remain, at best, speculative. 

One of the most ferocious debates surrounding the etiology of neurodegenerative disorders concerns the relative roles of genetic and environmental factors in the initiation of these diseases. Some neurodegenerative disorders have a clear familial occurrence, suggesting a genetic basis. In addition to these “pure” genetic neurodegenerative diseases, others are essentially sporadic but show a small contingent of patients in whom the illness is inherited. This is true for PD, AD, and even ALS, of which about 10% of all cases are unequivocally familial. Although rare, these familial cases represent powerful resources to elucidate the molecular bases and, more importantly, the neurodegeneration mechanisms of their respective sporadic variants.

Common pathological mechanisms shared by Alzheimer's disease (AD ...
Pathological Hallmarks in Neurodegeneration. Creative Commons.

The key pathological hallmarks of neurodegenerative diseases include oxidative stress, proteasomal impairment, mitochondrial dysfunction, and accumulation of abnormal protein aggregates. Advances in the field of etiology and therapy are mainly based on understanding of basic biochemical and molecular events underlying degeneration in human post mortem brain specimens and animal models. Molecular imaging and the emergence of complex bioinformatics tools have provided important insights.

PARKINSON’S DISEASE

It is one type of neurodegenerative disease. When neurons die in a part of the brain called the Substantia nigra movement problems appear. The substantia nigra (Latin for “black substance”) is a region within the brain that contains a large number of neurons that release a substance called dopamine. By releasing dopamine, the neurons of the substantia nigra communicate with movement-producing parts of the brain, like the frontal lobe and the basal ganglia (clusters of neuron cell bodies). The basal ganglia are located deep in the centre of the brain and are made up of several different groups of neurons. Neuronal death in the substantia nigra means that these groups of neurons can no longer work properly, causing stumbling and shaking in the people that have this disease. These individuals also experience problems starting and maintaining their movements. 

HUNTINGTON’S DISEASE

Like Parkinson’s Disease, this is also a neurodegenerative disease that causes movement problems and affects the basal ganglia. Unlike Parkinson’s Disease, Huntington’s Disease is a genetic illness. This means that if either parent has the disease, the children are also very likely to have the illness. Huntington’s Disease is a result of abnormal protein build up in brain, which results in neuronal death, causing the movement disorder. Mainly, individuals with this disease will show excessive movement, movement that is generally unwanted and unnecessary. For example, they often have constant vibrating limbs, something that is out of their control. As the disease progresses, people with Huntington’s will find it increasingly hard to move the way they want to move.

DEMENTIA

Dementia is a general term for memory loss. Two common types of dementia are Alzheimer’s Disease and Lewy Body dementia. Every type of dementia is a result of neurodegeneration (shrinking of the brain). Shrinking is caused by a lot of neuronal death occurring throughout the brain. Because of the large number of neurons dying, people with dementia not only start losing their memories, but they eventually lose their ability to move, communicate, and even think properly. 

Frontiers | Tau Propagation as a Diagnostic and Therapeutic Target ...
Tau Pathology. Frontiers.

In any neurodegenerative disease, if neurons are dying, then the brain is getting smaller! This is a serious problem and causes the person to have memory loss and thinking problems. These problems are a common feature of all neurodegenerative diseases.

The cardinal challenge in neurodegeneration is to either slow down or reverse disease progression. Extracts of naturally occurring agents theoretically may have less toxicity compared to synthetic drugs. F. Ghahremanitamadon et al. demonstrate the shielding efficacy of Borago officinalis extract in amyloid β-peptide (25–35)-induced oxidative stress and behavioural deficits. They demonstrate the usefulness of Borago officinalis extract in reducing memory impairment. 

One of the most exciting ideas that scientists are currently working on is to replace the dead neurons in the brain with new ones. Replacing dead neurons can be done using a special type of cell called stem cells. Stem cells are immature cells that can become any type of cell in the body, which is why they can act as a replacement for dead neurons in the brain.

IJMS | Free Full-Text | Neurodegeneration and Neuro-Regeneration ...
Stem Cells as an Intervention Strategy. MDPI.

Another major difficulty is to effectively deliver an active or pro drug across the blood-brain barrier. The blood-brain barrier usually allows only specific molecules to pass, hence, drug delivery becomes difficult to modulate. But clinical trials are ongoing for some drugs which has shown success in this regard.

Diagnosis and delineation of neurodegeneration are still complicated. A. P. Patterson et al. highlighted the relevance of in vivo optical imaging systems in neurodegeneration. The contribution of imaging tools along with fluorescent and bioluminescent molecules, in the diagnosis and monitoring of neurodegenerative diseases is indelible. 

Over the past two decades, significant advances in neuro-histological techniques such as immunohistochemistry have replaced or supplemented many of the classical histological approaches. Unquestionably, these new techniques have improved the sensitivity and specificity of neuropathological diagnostic criteria and consequently the accuracy of classification of neurodegenerative disorders.

Brain Imaging for Alzheimer's & Dementia | Pacific Brain Health Center
Amyloid and Tau Imaging. Source PsyPost

Over the course of several years, the key studies on neurotransmitters were integral in exploring mechanisms of neurodegeneration. Traditional staining has now metamorphosed into modern imaging techniques. Advances in genetic tools have enabled ease of generating effective animal models in research. Needless to mention, drug design has been revolutionised and from this in turn, stems the hope that one day we will uncover fundamental insights into the curse of neurodegeneration.

Preventing Neurodegeneration by Taking Care of the Brain | Natural ...

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