Neurodegenerative Diseases (NDDs)
By Ishwari Bhattacharya | 1 October 2024
Introduction
Regeneration is one of nature’s most captivating feats.
It's a testament to the resilience and adaptability of life. A planarian worm (eg. Taenia solium (pork tapeworm)), can be cut into many pieces and each piece will regrow into a full worm within about two weeks. Although the regenerative capacity in human beings is limited, it plays a significant role in our everyday lives.
Ironically, the most important and intricate cells of our body, the nerve cells or neurons have very limited regenerative capacity. Neuroregeneration is defined as the regrowth or repair of nervous tissues,cells or cell products. Neuroregenerative mechanisms may include generation of new neurons, glia, axons, myelin, or synapses. Neuroregeneration differs between the peripheral nervous system (PNS) and the central nervous system (CNS) (that is, the brain and spinal cord) with regards to the functional mechanisms involved, especially in the extent and speed of repair. Unlike a peripheral nervous system (everything apart from the brain and spinal cord) injury, injury to the central nervous system is not followed by extensive regeneration.
Neurodegeneration is defined as a complex process that causes death of neurons in the brain and spinal cord, resulting in damage and dysfunction. Chronic neurodegeneration leads to neurodegenerative diseases, a condition that damages and destroys parts of our nervous system over time, especially our brain. These conditions are permanent and incurable.
The most common NDDs include Alzheimer’s disease, Parkinson’s disease, prion disease, Amyotrophic lateral sclerosis (ALS), motor neuron disease, Huntington’s disease, spinal muscular atrophy, and spinocerebellar ataxia.
Common causes and symptoms of NDDs
Some neurodegenerative diseases have a single cause that healthcare providers can identify. But in many cases, this isn't the case. Instead, research shows that multiple factors probably contribute to neurodegenerative diseases, which may even be undetectable.
So far, experts have generalized some possible causes or risk factors, like:
- Age: These conditions have strong ties to age. The older you are, the greater your chances of developing one. Some degenerative brain diseases can start earlier in life, but this is less common.
- Genetics: Many neurodegenerative diseases have strong ties to family history. That’s often because of specific mutations you can inherit that increase your risk. Spontaneous mutations can also happen, and sometimes a combination of genes plays a role.
- Environment: Our environment can be a major factor in developing these conditions. for example, lower vitamin D levels, which are more common the farther you live from the Earth’s equator, have links to dementia-type diseases
- Medical history: Some neurodegenerative conditions can either happen because of specific medical events or can get worse because of them. Some examples include cancer, certain types of infections, if you've had head injuries and more.
- Habits, routines and choices: daily lifestyle, use and abuse of drugs and hallucinogens and an overall unhealthy life can very likely lead to such conditions.
The symptoms of neurodegenerative diseases can vary widely, even among people with the same condition. There are a few reasons for this. Firstly, each person’s brain is unique. No two brains form or work in exactly the same way. That means the same condition can still affect two people differently. Further, neurodegenerative diseases happen for many different reasons. The possible causes can vary widely for these conditions, even among conditions of the same type. The symptoms depend the parts of your brain or nervous system affected.
Alzheimer’s Disease
Alzheimer's disease is alarmingly prevalent and has a significant impact globally.Over 55 million people worldwide are living with dementia and Alzheimer's disease contributes to 60-70% of these cases. Alzheimer's disease is a significant cause of morbidity and mortality among the elderly in India. While exact statistics on Alzheimer's as a cause of death can vary, it is known to be one of the leading causes of dementia, which affects over 1 million individuals in the country.
Symptoms
The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation,self-neglect, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the average life expectancy following diagnosis is three to twelve years.
Causes
The cause for most Alzheimer's cases is still mostly unknown, except for 1–2% of cases where deterministic genetic differences have been identified. Several competing hypotheses attempt to explain the underlying cause; the most predominant hypothesis is the amyloid beta (Aβ) hypothesis.
When abnormal amounts of amyloid beta (Aβ) protein accumulate extracellularly as amyloid plaques and tau proteins, or inside the cell as neurofibrillary tangles in the brain, it affects our brain's neuronal functioning and connectivity, resulting in a progressive loss of brain function. This altered protein clearance ability is age-related, regulated by brain cholesterol, and associated with other neurodegenerative diseases.
Pathophysiology
Alzheimer's disease is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross wasting away of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.
Upon postpartum inspection of the brain of the affected patients, both Aβ plaques and neurofibrillary tangles(NFTs) are clearly visible in microscopy especially in the hippocampus. However, Alzheimer's disease may occur without neurofibrillary tangles in the neocortex.
Aβ plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Neurofibrillary tangles (NFTs) are aggregates of the microtubule-associated protein (MAP) tau which has become hyperphosphorylated (excessive and unnatural addition of phosphate groups) and accumulate inside the cells themselves.
However, recent studies show that beta-amyloid protein deposition starts decades before the first clinical symptoms. Furthermore, based on the assessment of the distribution of neurofibrillary tangles (NFTs), subtypes of Alzheimer's disease - for example hippocampal sparing, typical or limbic-pre dominant -- have been proposed, arguing for further subclassification of AD.
In summary, for the current neuropathological diagnosis of Alzheimer's disease , based on the recommendation of the National Institute on Aging-Alzheimer’s Association, an ‘ABC’ score, for the description of Alzheimer's disease induced neuropathological change, has been adopted.
- Score A for ‘amyloid’: incorporates the phases of Aβ deposition.
- Score B for ‘Braak’: integrates stages of tau-positive neurofibrillary degeneration.
- Score C for ‘CERAD’: credits the extent of appearance of argyrophilic neuritic plaques.
The ABC score put together classifies the neuropathological changes by the disease into 4 levels: not, low, intermediate or high.
References
- Lamptey RN, Chaulagain B, Trivedi R, Gothwal A, Layek B, Singh J; A Review of the Common Neurodegenerative Disorders: Current Therapeutic Approaches and the Potential Role of Nanotherapeutics; Int J Mol Sci; February 2022
- Patow, Gustavo; Escrichs, Anira; Ritter, Petra; Deco, Gustavo; Whole-Brain Dynamics Disruptions in the Progression of Alzheimer's Disease: Understanding the Influence of Amyloid-Beta and Tau"; bioRxiv; March 2024
- Erkkinen, Michael G.; Kim, Mee-Ohk; Geschwind, Michael D. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harbor Perspectives in Biology. April 2018
- Image: Maropeng Visitor Center