The concept of diminished functional reserve
One of the most significant explanations for why age is a predisposing factor for delirium lies in the concept of diminished functional reserve. The brain's reserve refers to its capacity to withstand stress and pathology while maintaining normal function. As the brain ages, it experiences a gradual decline in this reserve due to various structural and functional changes. When an older adult is faced with a physiological stressor—such as an infection, surgery, or dehydration—the brain's diminished capacity to compensate can be overwhelmed, leading to the acute and reversible syndrome of delirium. In younger, healthier individuals with higher brain reserve, the same stressor might cause less severe or no cognitive changes at all.
Brain aging reduces neuronal connectivity
Normal brain aging involves several changes that weaken neuronal networks and connectivity, which are essential for complex cognitive processes. One key change is a reduction in synapses—the connections between neurons—which impairs communication throughout the brain. Additionally, there is a loss of myelinated axons, which insulate and protect nerve fibers, further slowing communication. These changes mean that the neural networks responsible for attention, memory, and executive function are more fragile and less resilient to acute disruptions.
Neurotransmitter imbalances and cholinergic deficiency
The delicate balance of neurotransmitters, the brain's chemical messengers, is often disrupted with age and is considered a primary mechanism behind delirium. The cholinergic deficiency hypothesis is particularly prominent. Acetylcholine, a neurotransmitter critical for attention, memory, and sleep-wake cycles, tends to decrease with age. This deficiency is exacerbated by anticholinergic drugs, which are commonly used to treat other conditions in older adults, further increasing the risk of delirium.
Other neurotransmitter systems are also implicated:
- Excess Dopamine and Norepinephrine: An imbalance can occur with relative excess of dopamine and norepinephrine compared to acetylcholine, contributing to the agitated or hyperactive symptoms seen in some forms of delirium.
- Serotonin and GABA: Alterations in serotonin and GABA (gamma-aminobutyric acid) levels can also contribute to the behavioral and cognitive changes of delirium.
The role of chronic and systemic inflammation
As people age, the immune system undergoes a process known as "inflammaging," a state of chronic, low-grade, and systemic inflammation. This process involves an increased production of pro-inflammatory cytokines, even without an active infection. When an acute stressor like an infection or surgery occurs, the aged immune system and resident brain immune cells (microglia) can mount an exaggerated inflammatory response.
Blood-brain barrier vulnerability
The blood-brain barrier (BBB), which normally protects the brain from harmful substances in the bloodstream, becomes more permeable with age. Chronic inflammation and stress can damage the integrity of the BBB, allowing inflammatory cytokines and other toxic molecules to enter the brain. Once inside, these substances can trigger further neuroinflammation, disrupting neurotransmitter balance and causing neuronal damage that precipitates delirium.
Polypharmacy and comorbidity
The presence of multiple chronic health conditions (comorbidities) and the use of numerous medications (polypharmacy) are common in older adults, significantly contributing to the risk of delirium. The more predisposing factors a patient has, the fewer precipitating factors are needed to trigger delirium.
Polypharmacy risk factors for delirium
- Increased drug interactions: Taking multiple medications increases the likelihood of drug-drug interactions that can alter drug metabolism or enhance side effects, including cognitive impairment.
- Higher anticholinergic burden: Many medications used by older adults have anticholinergic properties (e.g., certain antidepressants, antihistamines, and bladder control medications) that block acetylcholine and can trigger confusion.
- Organ dysfunction: Age-related declines in kidney and liver function can lead to impaired drug clearance, causing medications to accumulate to toxic levels and precipitate delirium.
Aging-related physiological changes
Beyond the brain, general physiological changes in the elderly make them more susceptible to the stressors that trigger delirium.
- Reduced Cerebral Blood Flow: Aging is associated with decreased cerebral blood flow (CBF), which can lead to tissue hypoxia and metabolic stress on neurons, especially during periods of low blood pressure or illness.
- Mitochondrial Dysfunction: Cellular respiration and energy production become less efficient with age due to mitochondrial dysfunction. Neurons are highly dependent on oxidative phosphorylation for energy, making them vulnerable to deficits and oxidative stress.
- Circadian Rhythm Dysregulation: Older adults often experience disrupted sleep-wake cycles and lower melatonin levels, which can impair brain function and increase vulnerability to delirium.
Comparison of Risk Factors for Delirium
| Feature | Younger Adults | Older Adults |
|---|---|---|
| Brain Reserve | High functional capacity; more resilient. | Diminished functional reserve; less able to cope with stress. |
| Neuronal Connectivity | Robust and efficient synaptic connections. | Decreased connectivity due to synapse loss and demyelination. |
| Neurotransmitter Balance | Stable balance, especially sufficient acetylcholine. | Imbalance common, notably cholinergic deficiency. |
| Immune Response | Controlled and efficient inflammatory response. | Pro-inflammatory state (inflammaging) leads to exaggerated response. |
| Blood-Brain Barrier (BBB) | More robust and impermeable barrier. | Increased permeability, allowing inflammatory markers to enter. |
| Cerebral Blood Flow | Stable and well-regulated blood flow. | Reduced blood flow and impaired autoregulation. |
| Comorbidity Burden | Fewer chronic health conditions. | Higher burden of chronic diseases (e.g., dementia, vascular disease). |
| Polypharmacy | Less frequent medication use. | High prevalence of polypharmacy and potential for drug interactions. |
Conclusion
In summary, the increased frequency of delirium in older individuals is not due to a single cause but is the result of multiple interconnected physiological changes that accumulate with age. The aging brain has a reduced capacity to withstand stressors due to declines in functional reserve, neuronal connectivity, and neurotransmitter function. This inherent vulnerability is compounded by an overactive inflammatory response and a compromised blood-brain barrier. Furthermore, the higher prevalence of chronic illnesses and polypharmacy in older adults significantly increases the risk, lowering the threshold for delirium to be triggered by acute events like illness or surgery. A comprehensive understanding of these age-related factors is essential for both prevention and management strategies, emphasizing multi-component interventions that address the underlying vulnerabilities of the older patient.
For more information, see the full article on aging and brain vulnerability from Springer.
