Brain in Peril: The Effect of Alzheimer’s On Plasticity#

By Megha Verma

Neuroplasticity , also known as neural/brain plasticity, is the brain’s ability to adapt, reorganize and rewire connections within itself. Plasticity occurs in response to external stimuli, learning, or even injury. Up until recently, scientists believed neuroplasticity only occurred during certain periods of an organism’s life. Now, scientists know neuroplasticity occurs throughout our entire lives and can even be induced and enhanced. Alzheimer’s disease and other forms of dementia can trigger significant neuroplastic changes in the brain. Some of these changes are beneficial, trying to repair the damage done by the disease, while others are harmful, locking in or exacerbating the cognitive losses. The present chapter will explore these neuroplastic changes, both beneficial and harmful, ending with an exploration of current plasticity-based treatment options offering hope to Alzheimer’s and dementia patients.

Alzheimer’s disease (AD) is characterized by memory deficits, cognitive impairments, and behavioral changes which are heavily connected to AD’s impact on the hippocampus. The hippocampus is one of the first brain regions to be affected by Alzheimer’s disease and other forms of dementia, which are characterized by progressive cognitive decline and memory loss. The hippocampus is a part of the brain that is involved in forming and retrieving memories, especially those related to facts and events (declarative memories) and spatial relationships (spatial memories). The damage to the hippocampus impairs its ability to process and store new information, as well as to access old information. A damaged hippocampus leads to symptoms such as forgetting recent events, getting lost in familiar places, and having difficulty learning new skills. The hippocampus also shrinks in size and volume as dementia progresses, which can be measured by brain imaging techniques. Additionally, the extent and rate of hippocampal atrophy can be correlated to the severity and progression of the disease.

The main pathological features of AD are the aggregated presence of extracellular amyloid-β (Aβ) plaques, and the neurofibrillary tangles made up of tau protein. Because of these features, there are essentially two schools of thought on what causes and drives the progression of the disease. The amyloid hypothesis has been one of the main theories; it says that the accumulation of beta-amyloid is the primary driver of the disease because of the neuroinflammation, synaptic toxicity, and neural death it causes. The tau hypothesis, on the other hand, suggests that it is actually tau that is the key factor in AD, and that its abnormal phosphorylation and aggregation cause neurotoxicity, impair axonal transport, and disrupt neuronal communication. While the amyloid hypothesis has been around for over two decades, the tau hypothesis is relatively newer and seems to provide more promising evidence when trying to slow the progression of the disease. Both hypotheses have been supported by genetic, biochemical, and animal studies, but also challenged by clinical trials that failed to show clear benefits of targeting Aβ or tau (Kametani, 2018). Therefore, the exact relationship between Aβ and tau, and their respective roles in AD pathogenesis and progression, remains somewhat unresolved and controversial. However, there are some patterns that establish correlations between neuropathology and the progression of the disease. The levels of beta-amyloid and tau proteins in the cerebrospinal fluid (CSF) are used for diagnosing AD and for phenotyping. Their concentrations may also be able to predict not only the progression of the disease, but the severity as well. Recent research has also shown that patients with high levels of the tau protein accumulation are more likely to have weakened brain structures and functioning, especially on a cognitive level. An overexpression of tau itself has been seen to be indicative of severe cognitive impairment too. Synaptic dysfunction is also usually seen before neural loss in brain regions, making it one of the early pathological signs of the disease. In this chapter, we will learn about neuroplastic changes related to Alzheimer’s and dementia. We will also explore the current challenges and future directions for developing effective therapies based on these changes.

Alzheimer’s and dementia are characterized by progressive cognitive decline and impairment, affecting memory, language, reasoning, and other mental functions. These diseases are caused by the accumulation of abnormal protein deposits called amyloid plaques and neurofibrillary tangles in the brain as mentioned, which interfere with the communication and function of neurons. As a result, the brain undergoes structural and functional changes, some of which are adaptive and some of which are maladaptive. Some of the adaptive changes are aimed at repairing or compensating for the damage caused by the Alzheimer’s disease. Reparative plastic changes can also try to enhance the remaining cognitive and behavioral functions of the brain. For example, some studies have shown that Alzheimer’s patients have increased neurogenesis (the formation of new neurons) in the hippocampus; possibly as a response to the neuronal loss and cognitive impairment caused by the disease. This increased neurogenesis could be a response to the neuronal loss and the cognitive impairment caused by the disease, or an attempt by the brain to replace the lost neurons and restore some of the memory functions of the hippocampus. Another example is the activation of alternative neural pathways or networks to perform cognitive tasks that are impaired by the disease, which could reflect the brain’s flexibility to cope with the challenges posed by Alzheimer’s. As it appears, increased neurogenesis may help to replace lost neurons and restore some memory functions, or it may provide a reserve of neurons that can be recruited for other cognitive tasks.

Note

Neuroplastic changes are not isolated to an age group, in fact, it’s been documented to happen in older individuals. One instance of a mature brain experiencing neuroplastic changes is seen in the case of patient X, a 31-year-old right-handed man. He was admitted to a hospital because of weakness in his left arm and a fainting episode. Despite these initial issues, his symptoms had almost entirely subsided when he was admitted; he had recovered almost all sensation and normal functioning. A full neurological workup showed no sensory deficits either. How did Patient X’s symptoms seem to resolve so quickly, and leave almost no medical trace behind?

Looking through Patient X’s past medical history, the doctors found that he had been hospitalized as a young child for a headache, vomiting, and a fever. Patient X was also experiencing neck stiffness when he was hospitalized. During this time, he underwent a ventriculography; the cerebrospinal fluid was removed from his ventricles and replaced with air to make imaging easier. Based on the imaging, Patient X was diagnosed with a long-term right subdural hygroma. Subdural hygromas are formed when the subdural space is filled with blood tinged or clear fluid. Patient X was also exhibiting serious sensorimotor deficits in his left arm and leg. These deficits seemed to resolve about two months after he was first hospitalized but were seen at the time when he was admitted as a 31-one-year old. However, there had not been any seizures reported in the last five years aside from the current episode. While he seemed to be recovering okay after the hospitalization at 12, he still had a severe right subcortical lesion. Despite this serious damage to his right hemisphere, Patient X was able to move both of his hands normally. Patient X also showed amazing reorganization of his brain; his premotor and sensorimotor cortices showed an increase in cerebral blood flow regardless of which hand he was moving. Patient X was showing actual functional plastic changes, even after severe brain damage that had occurred quite early in his life. Where one might assume that such changes would be out of the realm of possibility given the time frame that the damage occurred, Patient X’s experience highlights how neuroplasticity is not limited to the youth and it stands to represent the wonders of the brain.

However, there are also maladaptive changes that occur from Alzheimer’s disease; changes that are detrimental and exacerbate the cognitive losses. Some studies have shown that Alzheimer’s patients have reduced synaptic plasticity (the ability of synapses to strengthen or weaken over time) in the cortex, a brain region involved in higher-order cognitive functions. This may reflect the loss of synaptic connections and the impairment of learning and memory processes. Another example is the overactivation or hyperexcitability of certain brain regions or circuits, which may lead to seizures, agitation, and hallucinations. This may reflect the imbalance of neurotransmitters and the disruption of normal brain activity and could be due to the aggregation of toxic protein deposits in the brain.

Neuroplasticity in Alzheimer’s and dementia is a double-edged sword, with both beneficial and harmful effects. Understanding these effects is crucial for developing effective treatments and interventions for these diseases. One promising avenue is to harness the positive aspects of neuroplasticity and minimize the negative ones, by stimulating or modulating the brain’s activity and function. For instance, some studies have shown that cognitive training, physical exercise, and social engagement can enhance cognitive performance and delay cognitive decline in Alzheimer’s and dementia patients, by promoting neurogenesis, synaptic plasticity, and neural network activation. Another example is the use of non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), which can modulate the brain’s excitability and plasticity, and improve cognitive functions such as memory, attention, and language in Alzheimer’s and dementia patients.

So far, scientists know that synaptic density loss precedes neuronal degeneration. Scientists also know that there is a strong correlation between the level of cognitive impairment and a loss in synaptic density. Thus, weakened synaptic transmission has the potential to predict the severity of the disease, instead of having to use the neuronal failure that occurs later. Since dementia is a group of symptoms rather than a single disease, multiple processes carried out by the brain are impacted. Currently, there are no cures for dementia, and the existing drug treatments have low success rates. Aside from drugs, there has been a spike in exploring non-pharmacological treatments (NPTs) as therapies for dementia. There are various forms of NPTs, most used are exercise and cognitive rehabilitation. Psychological therapies can also be used to target the behavioral aspects of the diseases. However, exercise seems to be the best intervention to slow the onset and even severity of dementia, based on the neuroplastic changes it can induce. Irisin, a hormone that is produced by the muscles during exercise, can directly impact the brain because it can cross the blood-brain barrier; it has also been shown to have the ability to prevent neural cell death, which can be used as a potential therapy for neurodegenerative diseases. In addition, Irisin can also stimulate the secretion of another hormone that is involved in neuroplasticity: brain-derived neurotrophic factor (BDNF). BDNF can regulate microglia activation leading it to have an anti-inflammatory effect on the brain. Furthermore, Irisin is able to modulate the communication between neurons, carry damaged cells away, and decrease the production of pro-inflammatory markers while increasing the expression anti-inflammatory genes. Thus, exercise seems to be a strong therapeutic intervention for slowing the onset and severity of dementia because of its cognitive benefits and neuroprotection.

Neuroplasticity is the ability of the brain to adapt and reorganize itself in response to various stimuli and experiences. Neuroplasticity is essential for normal brain development, learning, memory, and recovery from injury. However, neuroplasticity can also be impaired or altered in pathological conditions, such as neurodegenerative diseases like Alzheimer’s disease and dementia that affect millions of people worldwide. The mechanisms underlying the impairment of neuroplasticity in Alzheimer’s disease and dementia are not fully understood, but they may involve the accumulation of abnormal proteins, such as amyloid-beta and tau, as well as inflammation, oxidative stress, mitochondrial dysfunction, and epigenetic modifications. These factors may disrupt the molecular and cellular processes that mediate synaptic plasticity, such as neurotransmitter release, receptor activation, intracellular signaling, gene expression, and cytoskeletal dynamics. These disruptions may contribute to the worsening of cognitive and functional outcomes in patients with Alzheimer’s disease and dementia, as well as to the resistance to pharmacological and non-pharmacological treatments. Therefore, targeting neuroplasticity may offer a novel and promising strategy for the prevention, diagnosis, and treatment of Alzheimer’s disease and dementia. In fact, several approaches have already been proposed or tested to enhance or restore neuroplasticity in these disorders, such as brain stimulation techniques, cognitive training, physical exercise, dietary interventions, and pharmacological agents. However, the efficacy and safety of these interventions are still under investigation, and more research is needed to identify the optimal parameters, timing, and combination of these interventions; in addition to the individual factors that may influence the response to neuroplasticity-based therapies. Furthermore, the development of reliable and valid biomarkers of neuroplasticity is essential for the evaluation of the effects of these interventions on the brain structure and function, as well as on the clinical outcomes. In conclusion, neuroplasticity is key to understanding and managing Alzheimer’s disease and dementia and through exploration of its mechanisms, neuroplasticity may give rise to new ways of preserving and enhancing the cognitive and functional abilities of patients with the conditions and, ultimately, improving their quality of life.

Chapter Quiz#

  1. What are the two main proteins that accumulate abnormally in the brains of patients with Alzheimer’s disease?

    • A. Tau and alpha-synuclein

    • B. Alpha-synuclein and beta-amyloid

    • C. Tau and beta-amyloid

    • D. Beta-amyloid and gamma-aminobutyric acid

  2. What is the name of the brain region that is responsible for the formation of new memories and is severely affected by Alzheimer’s disease?

    • A. Hippocampus

    • B. Amygdala

    • C. Cerebellum

    • D. Thalamus

  3. What is the term that describes the ability of the brain to adapt and reorganize itself in response to various stimuli and experiences?

    • A. Neurogenesis

    • B. Neurodegeneration

    • C. Neurotransmission

    • D. Neuroplasticity

  4. What are the two main types of memory that the hippocampus is involved in forming and retrieving?

    • A. Procedural and semantic

    • B. Declarative and spatial

    • C. Working and long-term

    • D. Implicit and explicit

  5. What are the two abnormal proteins that accumulate in the brain of patients with Alzheimer’s disease and may impair neuroplasticity?

    • A. Amyloid-beta and tau

    • B. Dopamine and serotonin

    • C. Glutamate and GABA

    • D. Insulin and glucagon

  6. What is the formation of new neurons called?

    • A. Synaptic pruning

    • B. Neurogenesis

    • C. Neuroplasticity

    • D. Amyloidosis

Answers#

  1. C.

  2. A.

  3. D.

  4. B.

  5. A.

  6. B.

References#

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