Geriatric Perspective: Sundown Syndrome and Dementia Diagnosis and Treatment

1. Introduction
SUNDOWNING SYNDROME (or twilight syndrome) and dementia are conditions that frequently affect older adults, presenting significant challenges to diagnosis and treatment. A comprehensive geriatric perspective based on the current under- standing of these conditions is offered below:

1.1. Symptoms
Sundowning syndrome is characterized by increased confusion, agitation, anxiety or disruptive behaviors in people with dementia, typically in the late afternoon or overnight. Symptoms include:
• Agitation or restlessness: Pacing, yelling or irritability.
• Increased  confusion: Difficulty  recognizing  familiar people or places.
• Sleep disturbances: Insomnia or reversal of the sleep-wake cycle.
• Delusions or hallucinations: In some cases, misperceptions of reality.

1.2. Diagnostic methods
The diagnosis is mainly clinical, as there is no specific test for

sundowning. Key steps include:
• Detailed medical history: Collect information from caregivers about the timing and nature of behaviors.
• Cognitive and functional assessment: Use tools such as the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA) to assess underlying dementia.
• Rule out other causes: Evaluate possible triggers such as:
• Infections (e.g., UTI).
• Untreated pain.
• Medication side effects.
• Metabolic disturbances (e.g., hypoglycemia, dehydration).
• Temporal pattern observation: Confirm whether symptoms intensify in the evening or overnight.

1.3.Treatment options
The management of sundowning combines non-pharmacological strategies and, in some cases, pharmacological interventions:
• Non-pharmacological (first line):
○ Structured routines: Maintain regular schedules for meals, activities and sleep.
○ Optimizing the environment: Reducing noise, providing adequate lighting during the day and decreasing excessive stimulation at night.
○ Calming activities: Soft music, aromatherapy or simple activities like folding laundry.
○ Daylight exposure: Encourage morning walks or the use of phototherapy boxes to regulate the circadian rhythm.
○ Avoid triggers: Limit caffeine, long naps and stressful events at the end of the day.

• Pharmacological (only if necessary):
○ Use with caution because of the risks in older adults.
○ Melatonin: May help regulate sleep, although evidence is mixed (dosage: 1-3 mg before bedtime).
○ Antipsychotics (e.g., risperidone, quetiapine): Reserved for severe cases with extreme agitation, in low doses and for a limited time due to the risk of adverse effects such as sedation or cardiovascular events.
○ Cholinesterase inhibitors (e.g., donepezil): These may be considered if the underlying dementia is Alzheimer’s.
○ Caregiver education: Teach management strategies, communication techniques and the importance of their own well-being.

ALTHOUGH ITS PATHOPHYSIOLOGY is not fully
elucidated due to its multifactorial nature and lack of specific studies, several mechanisms that interact with each other have been proposed. The main pathophysiological mechanisms involved are described below, based on the evidence available up to April 2025.

1.3.1. Circadian rhythm disturbances:
• Description: The biological clock, regulated by the suprachiasmatic nucleus (SCN) in the hypothalamus, controls circadian sleep-wake rhythms, body temperature and hormone release. In dementia, especially Alzheimer’s disease (AD), the SCN has neuronal degeneration, which alters these rhythms.

• Specific mechanisms:
○ SCN degeneration: Post-mortem studies have shown neuronal loss and accumulation of amyloid plaques in the SCN in patients with AD, reducing its ability to synchronize circadian rhythms with the light-dark cycle.
○ Melatonin disruption: The production of melatonin, which regulates sleep, decreases with age and is aggravated in dementia. Nocturnal melatonin secretion is suppressed, contributing to insomnia and evening agitation.
○ Environmental desynchronization:  Less exposure to daylight (due to institutionalization or reduced mobility) weakens the external signals (zeitgebers) necessary to maintain the circadian rhythm, exacerbating confusion at dusk¹.

1.3.2.Neurotransmitter dysfunction:
• Description: Alterations in neurotransmitter systems, such as cholinergic, serotonergic and dopaminergic, contribute to the behavioral and cognitive symptoms of sundowning.

• Specific mechanisms:
○ Cholinergic deficiency: In AD, the loss of cholinergic neurons in the basal Meynert nucleus and prefrontal cortex reduces the activity of acetylcholine, a key neurotransmitter for attention and memory. This deficiency can exacerbate confusion at the end of the day, when the cholinergic system is under greater stress.
○ Serotonin disturbances: The decrease in serotonin, seen in dementia, affects mood and sleep regulation. The drop in serotonin at the end of the day can contribute to the anxiety and agitation characteristic of sundowning.
○ Dopaminergic dysregulation: In dementias such as Lewy body dementia, dopaminergic fluctuations can cause hallucinations and evening agitation. The interaction between dopamine and melatonin can also destabilize the sleep-wake cycle².

1.3.3. Oxidative stress and neuroinflammation:
• Description: Neurodegeneration in dementia is associated with increased oxidative stress and chronic inflammation in the brain, which may amplify the symptoms of sundowning.

• Specific mechanisms:
○ Accumulation of reactive oxygen species (ROS): Oxidative damage in regions such as the hippocampus and prefrontal cortex affects emotional and cognitive regulation, increasing vulnerability to episodes of confusion at the end of the day.
○ Microglial activation: Therelease of pro-inflammatory cytokines (e.g., IL-6, TNF-α) by activated microglia contributes to synaptic dysfunction and may exacerbate agitation during times of fatigue or sensory overload.
○ Interaction with circadian rhythms: Inflammation alters the expression of clock genes (e.g., CLOCK, PER2), further desynchronizing the circadian rhythm³.

1.3.4. Cognitive overload and fatigue:
• Description: Sundowning may be related to the accumulation of cognitive and physical fatigue throughout the day, which exceeds cognitive reserve capacity in patients with dementia.

• Specific mechanisms:
○ Depletion of cognitive resources: Daily cognitive demands (social interactions, activities) deplete executive functions, especially in the prefrontal cortex, resulting in emotional dysregulation at the end of the day.
○ Hyperactivity of the hypothalamic-pituitary- adrenal (HPA) axis: Accumulated stress activates the HPA axis, increasing evening cortisol levels, which can induce anxiety and confusion.
○ Reduced cortical inhibition: Fatigue decreases the ability of the prefrontal cortex to inhibit impulsive emotional responses, contributing to agitation⁴.

1.3.5. Sensory and perceptual alterations
• Description: Visual and auditory deficits, common in older adults, can exacerbate confusion in low-light or high- stimulation settings at dusk.

• Specific mechanisms:
• Decreased visual acuity:  Reduced light at the end of the day makes it difficult to perceive the environment, increasing disorientation and anxiety.
• Impaired sensory processing: In dementia, the processing of visual and auditory stimuli is compromised, which can lead to misinterpretations (e.g., shadows perceived as threats).
• Interaction with hallucinations: In Lewy body dementia, alterations in the visual pathway (occipitoparietal cortex) can generate evening hallucinations, contributing to sundowning⁵.

1.3.6. Systemic factors and comorbidities
• Description: Underlying medical conditions may interact with neurodegeneration to exacerbate sundowning.
• Specific mechanisms:
• Untreated chronic pain: Pain (e.g., from arthritis) may intensify at the end of the day, contributing to restlessness and agitation.
• Infections or metabolic imbalances: UTIs, hypoglycemia or dehydration can trigger or aggravate evening symptoms by disturbing the homeostatic balance.
• Drug effects: Some drugs (e.g., benzodiazepines, anticholinergics) alter alertness or sleep, increasing vulnerability to sundowning⁶.

1.4. Interaction de mechanisms
El sundowning resulta de la convergencia de estos mecanismos en un contexto de vulnerabilidad cerebral. Por ejemplo:
•  La degeneración del NSQ y la disminución de melatonina desregulan el sueño, lo que aumenta la fatiga cognitiva.
• La fatiga, combinada con déficits colinérgicos y sensoriales, reduce la capacidad de procesar estímulos ambientales, desencadenando ansiedad.
• La neuroinflamación y el estrés oxidativo amplifican la disfunción neuronal, mientras que comorbilidades sistémicas actúan como desencadenantes adicionales.
• Factores externos, como la disminución de luz o un entorno ruidoso, interactúan con estas alteraciones biológicas para precipitar los síntomas.

1.5. Limitations in knowledge
• Lack of specific studies: Most of the data comes from general dementia research, not studies designed for sundowning.
• Clinical heterogeneity: Symptoms vary between patients and types of dementia (Alzheimer’s, Lewy bodies, vascular), complicating the identification of universal mechanisms.
• Limited animal models: Current models do not fully replicate sundowning, making experimental validation difficult.

1.6. Conclusion
Sundowning is the result of a complex interaction between circadian disturbances, neurochemical dysfunction, oxidative stress/inflammation, cognitive fatigue, sensory deficits and systemic comorbidities. Degeneration of the suprachiasmatic nucleus and cholinergic deficiency are central, but external factors and the progression of dementia modulate the expression of symptoms. Understanding these mechanisms allows for the design of targeted interventions, such as optimizing ambient light, pain management or cautious use of melatonin, although more research is needed to elucidate the specific pathways and develop more effective treatments (Table 1).

Table 1: For Visual Representation.