NEURODEGENERATIVE DISORDERS

PRESENTED BY:SYED MUDABIR AHMAD

What is Neuroscience?• Neuroscience, also known as Neural Science, is the study of how the

nervous system develops, its structure, and what it does.

• Brain, the controlling unit of the body comprise of billions of cells (neurons) which form the communication centre (nervous system).

• Neurons: Specialised cells, convey sensory information into the brain, transmit commands from the brain to control organs and muscles, thought, feeling and movement.

The progressive loss of nerve structure and function is called as neurodegeneration, which leads to the loss of cognitive abilities such as memory and decision making.

Neurons, the building blocks of the nervous system which includes the brain and spinal cord, normally doesn’t reproduce or replace themselves when damaged or die. 

Neurodegeneration is a key aspect of a large number of diseases that come under the umbrella of “neurodegenerative diseases.” Of these different disorders, the most notable being Alzheimer’s disease, Parkinson’s disease and Huntington disease.

Although these three diseases manifest with different clinical features, the disease processes at the cellular level appear to be similar.

Neurodegeneration

Alzheimer’s disease is a progressive neurodegenerative disease that mostly affects patients in their later stage of life.

Typical symptoms of Alzheimer’s disease are loss of cognitive functions including emotion, learning and memory processing skills leading to dementia.

About 70% of the risk is believed to be genetic with many genes involved. Other risk factors include a history of head injuries, depression, or hypertension.

Alzheimer’s disease

The pathological impression of Alzheimer’s disease can be characterised by the deposition of amyloid-beta (Aβ) protein plaques in the brain parenchyma and accumulation of tau proteins within neurons.

These protein plaques interfere with synaptic transmission and neuron-neuron communication leading to neuronal death.

tau proteins within neurons form tangles and block transportation of nutrients or other vital cellular factors throughout the cell which becomes reason for cell death in Alzheimer’s disease .

Pathology

Symptoms

Parkinson’s disease is typically considered a chronic, progressive neurodegenerative movement disorder.

Parkinson’s primarily cause death of the vital nerve cells in the area of brain called substantia nigra.

Some of these dying neurons produce dopamine which acts as messenger and sends message to the part of the brain that controls the movement and coordination.

As the Parkinson’s disease progresses the amount of dopamine produced from the brain decreases, leading a person unable to control movement normally.

Parkinson’s disease

Further, proteosomal and lysosomal system dysfunction and reduction in mitochondrial activity due to genetic mutations also cause cell death.

Activated neurons over expressing some proteins lead to early activation of microglia and release of various inflammatory mediators such as IL-1, IL-6 and TNF-α and also the reactive oxygen/nitric oxide species and prostaglandins enhance oxidative stress and trigger cell-death pathways

Symptoms

Multiple sclerosis is a chronic neuroinflammatory, progressive, degenerative disorder of the CNS characterized by demyelination of nerve fibers of the brain and spinal cord affecting people mostly between of 20 and 40.

Initially triggered by a virus in genetically susceptible individuals

Subsequent antigen-antibody reaction leads to demyelination of axons i.e; autoimmunity .

Multiple sclerosis

FatigueDepressionMemory changePainSpasticityTremorDouble Vision/Vision Loss

WeaknessDizziness/UnsteadinessNumbness/TinglingAtaxiaSpeech disturbanceBladder/Bowel/Sexual

dysfunction

Symptoms

Huntington’s disease is a rapidly progressive neurodegenerative disease that leads to dementia.

Typically presents with alterations in mood as well as a change in character, defects in memory and attention.

Progresses to a movement disorder consisting of involuntary and rapid motions.

Usually not recognized until the patient is in their early 30’s.

There is a 50% chance that a child whose parent has Huntington's will have the disease.

Huntington’s disease

It is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin, which means any child of an affected parent has a 50% risk of inheriting the disease

The faulty gene that causes Huntington's disease is found on chromosome number four.

The normal copy of the gene produces a protein called huntingtin, but the faulty gene contains an abnormal region of what are called CAG repeats. This area is larger than normal and produces a mutant form of huntingtin. 

Genotype/Phenotype

The expanded ployglutamine region of the pathological form of the protein causes impairment of the ubiquitin-proteasome system.

This means that the dysfunctional protein is not removed and destroyed as it should be.

Cells in parts of the brain- specifically, the basal ganglia and parts of the cortex are very sensitive to the effects of the abnormal huntingtin. This makes them function poorly and eventually die.

Pathological protein changes

The accumulation of the abnormal protein is believed to be what causes neurological changes.

The excess of the mutated protein interferes with neurotransmitters.

The brain normally sends messages through the basal ganglia and cortex to control movement and thinking, as well as motivation. If this part of the brain is damaged, it causes problems with control of movement, behaviour and thinking.

It's still unclear exactly how abnormal huntingtin affects the brain cells and why some are more sensitive than others.

Lack of physical activity, dietary problems, and eating and swallowing problems can cause constipation, weight loss and depression.

Pathology

• Choreic movements• Twitching• Balance problems• Tracking problems • Rigidity and dystonia

1. Movement symptoms

2. Cognitive

As Huntington's disease progresses, the ability to concentrate becomes more difficult

May have difficulty driving, keeping track of things, making decisions, answering questions, and may lose the ability to recognize familiar objects.

Over time judgment, memory, and other cognitive functions begin to deteriorate into dementia.

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3. Psychiatric Early psychiatric symptoms of Huntington's disease are subtle, varied, and easily

overlooked or misinterpreted

Depression is the most common psychiatric symptom and often develops early in the course of the disease. Signs of depression include:

- Hostility/irritability - Inability to take pleasure in life (anhedonia)

-Lack of energy - Hallucinations

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A major hallmark of neurodegenerative diseases is the abnormal deposition of

aggregates of misfolded proteins (proteinopathies) that lead to cell dysfunction and

eventually cell death (Wakabayashi and Tanji, 2009).

Imbalanced defense mechanism of antioxidants, overproduction or incorporation of

free radicals from environment to living system leads to serious functional or

sensory loss in neurodegenerative diseases (Raymund AC Roos 2010).

The protein plaques are able to evade degradation mechanisms and initiate a series

of neurotoxic effects, including synaptic dysfunction and disruption of cellular

organelles and the cytoskeleton, enabling an inflammatory response and ultimately

leading to cell death. (Lee, Lim, and Masliah.,2011).

Review of literature

Infiltration of lymphocytes into the CNS during neurodegenerative diseases initiate

inflammatory responses, neuronal injury and neurotoxicity in CNS (Shrestha and

Shakya 2014)

The accumulation of protease-resistant misfolded including the ubiquitin-proteasome

system, chaperone mediated autophagy and macroautophagy and aggregated proteins

is a common mechanism underlying neurodegenerative diseases (Aaron and Yong

2015).

Prevalence rate of dementia is tightly linked to ageing, neurodegenerative diseases

become more prevalent with age being accompanied by progressive motor and

cognitive impairment (Marina et al.,2016).

Continued…

Understanding of the genetics and initial symptoms and signs associated with neurodegeneration.

Studying pathophysiology and identification of an accessible tissue biomarker prior to symptom development.

Improved tests for identifying the conditions so they can be detected before too much neuronal loss has occurred.

The identification of sub-populations that have the best response to certain treatments so that the disease can be stopped as early as possible in responsive patients.

To find the best care for all patients and at-risk persons at this point in time.

My Area Of Interest

Mori H, Kondo J, Ihara Y (1987)- Ubiquitin is a component of paired helical filaments in Alzheimer's disease Vol. 235 ( 4796) , 1641-1644

Masliah E (1995) - Neurodegeneration in the Central Nervous System of apoE-Deficient Mice, Elesevier, Vol. 136, 107–122

Kevin, Colin (2004) - Neurodegenerative diseases and oxidative stress, Nature 3, 205-214.

Mattson, M.P (2004)- Pathways towards and away from Alzheimer’s disease. Nature, 430(7000): 631-639.

References

Michael, Flint (2006)-Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, Nature, 443, 787-795.

McFarland, H.F., Martin R (2007). Multiple sclerosis: A complicated picture of autoimmunity. Nat Immunol., 8(9): 913-9.

DeLegge M.H., A. Smoke (2008)- Neurodegeneration and inflammation, Nutr Clin Pract, 23(1): 35-41.

Engelhardt, B (2010) - T cell migration into the central nervous system during health and disease: Different molecular keys allow access to different central nervous system compartments, Clinical and Experimental Neuroimmunology, 1(2): 79-93.

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