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March's Tip: Evidence of Pineal Gland Calcification on CBCT is Not Insignificant: What Else You Might Discover about Your Patient

By: Dr. Stacy Fore

Many dental practices utilize a CBCT to examine and evaluate patients. These scans are then evaluated by a radiologist. A review of these reports often reveal that a radiopacity is noted in the midsagittal plane posterior and superior to the sella tursica compatible with calcification of the pineal gland. It is often reported that these findings have no clinical significance and follow —up/clinical correlation is not required. The following paper offers a review of anatomy and purpose of the pineal gland. It is intriguing that this tiny rice-sized gland has such a broad range of functions and influence. Of particular interest with the increase in research and treatment of sleep disorders is the pineal gland and melatonin production. A further review of the literature may encourage practitioners that these calcifications may be of clinical significance and warrant further follow-up.

Anatomy of the Pineal Gland:
The pineal gland is a small pine cone-shaped endocrine gland that produces melatonin. It is part of the epithalamus and located near the middle of the brain between the two halves of the thalamus. It is the only section of the brain to exist as a single part rather than half of a pair. It is not isolated from the body by the blood brain barrier and has a profuse blood supply second only to the kidney. The human pineal contains neurons, nerve fibers, and glial cells in an organization characteristic for neural tissues. The "capsule" of the organ is the continuation of the diencephalic meninges and is comprised of arachnoid and pia matter. The gland is innervated by the superior cervical, the pterygopalatine, otic, and trigeminal ganglion. The pineal gland has a common evolutionary origin to the retina. The interior of the gland contains retinal tissue composed of rods and cones wired to the visual cortex. The pineal develops by folding of its wall and has been considered a "folded retina," having both neural and hormonal outputs.'

Functions of the Pineal Gland:
The pineal gland is involved in many cellular processes. Bailey and colleagues found that 334 genes are expressed greater than 8 fold higher in the pineal gland relative to other tissues. Of these genes, 17% were also expressed in the retina. Many of these genes were found to be night/day differentially expressed in the pineal gland. Functional categorization of the highly expressed and or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune, inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. The study provided evidence of metabolic pathways and functional capacities of the pineal gland that were previously unrecognized. One function of the pineal gland is to produce melatonin, which then has influence on the timing of puberty and the regulation of our circadian and seasonal sleep patterns. The pineal gland translates light input from the retina into chemical signals for the rest of the body by secretion of melatonin. Melatonin is believed to play a part in microcirculation and blood pressure modulation through vasodilation, regulation of immune defense responses, as well as antioxidant effects.

Calcification of the Pineal Gland:
It is well-documented that calcification of the pineal gland is common and increases with age. Pineal calcifications, also called "acervuli," or brain sand, have been found to be calcified concretions of hydroxyapatite, composed mostly of calcium and magnesium salts. It has been reported from CT surveys that the most common intracranial physiological calcification was in the pineal region and was found more in males than in females. Calcification of the pineal gland has been shown to vary in different populations and is believed to be influenced by nutritional or environmental conditions. It has been hypothesized that calcification may cause neurodegeneration, which affects the gland volume. In addition, hormonal and genetic factors or a hypofunctional pineal gland may be involved in this structural change as well.' Available data document that calcification is an organized, regulated process rather than a passive aging phenomenon, and mast cells play a key role in the calcification process. Maslinska 's research results lead to the conclusion that the tryptase mast cells are the main players in the pineal calcification as the sites where this process starts and as a place of production of the biologically active substances including tryptase that participate in calcification. Research has shown that calcification of pinealocytes results from death or degeneration of the cell itself, thus leading to an overall decrease in pineal activity. There is also evidence that with age there is a decrease in functioning light pinealocytes and an increase of dark pinealocytes, which are characterized by intranudear deposition of calcium. The evolution and development of the pineal gland may make this gland susceptible to calcification. The pineal develops by folding of its wall and may increase the accumulation of calcium deposits due to difficulty of calcium ions to penetrate the layers of the gland. Pineal calcification has been associated with various diseases, including multiple sclerosis, schizophrenia, affective disorders, Alzheimer's disease, and sleep disorders. Kitkhuandee8 found that the risk of cerebral infarction increased 1.35 fold when pineal calcification was present. Studies have also shown a higher pineal gland calcification in migraine patients.

What are Some of the Possible Effects of Reduced Melatonin Production?:
Melatonin has many roles. Melatonin is a powerful antioxidant, anti-inflammatory, and contributes to circulation and blood pressure control via vasodilation along with playing a role in immune defense responses. Melatonin has been shown to inhibit cancer cell growth by tumor inhibition. In the oral cavity, melatonin participates in proliferation and remodeling of bone. Melatonin is capable of promoting differentiation and mineralization of preosteoblastic cells. Melatonin has the clinical application for use in reversing damage to osteoblasts caused by pathological conditions and disease. It may accelerate bone formation at bone graft sites. Melatonin is able to influence many cells and organs because it is amphiphilic, which enables it to enter all organs and subcellular compartments. Melatonin is estimated to detoxify up to 10 radicals and has equal or better efficacy in protecting tissues from oxidative injury as compared to vitamins C and E. It is also selective for mitochondrial membrane which is not shared by other antioxidants." Studies have found that migraine patients had a significantly higher pineal gland calcification compared with control subjects, and the calcifications did not show age- related increase. The increase in headache was possibly due to low levels of melatonin creating hyperactivity of the trigeminovascular system that leads to vasodilation and cerebral inflammation.

Pineal Gland and Sleep:
The pineal gland has been studied extensively as it relates to sleep. Reports measuring the volume, amount of calcification, and production of melatonin have all shown evidence that the gland can have a profound effect on sleep.. Pineal gland volume appeared to be reduced in patients with primary insomnia

compared to healthy controls. Smaller pineal gland volume has been shown to be a result of increased calcifications, and these abnormalities may lead to a disruption in melatonin secretion, disturbed circadian rhythmicity in the sleep wake cycle, and increase in daytime tiredness.

Kunz, et al demonstrated that the degree of pineal calcification is correlated negatively with total sleep time and sleep efficiency. Most changes were found to involve circadian rhythm disturbances with patients reporting an increase in daytime tiredness. Bumb, et al found that next to genetic and early life environmental factors, an increase of dysfunctional tissue (calcification) may contribute to low pineal gland volume as a predisposing factor of primary insomnia. Pineal gland calcification is often considered a part of the normal aging process, but they also found that even after adjusting for age, there was a significant correlation between pineal gland volume and REM latency in insomnia patients.  Mean REM latency was shorter in insomnia patients, reflecting substantial disturbances of normal sleep processes. Pineal gland calcification has also been shown to cause a decrease in melatonin production. Melatonin influences sleep onset and maintenance. Jan, et al found similarity exists between spindle behavior, circadian rhythmicity, and pineal melatonin production throughout life. Spindles play an active role in inducing, maintaining, and advancing NREM sleep towards deeper stages. During the night, low frequency spindles peak close to the height of melatonin levels and/or to the nadir of body temperature. Spindle evolution, like melatonin production, is also an index of neural development. A delayed appearance of spindles is associated with impaired brain maturation, delayed onset of circadian rhythms, and deferred melatonin secretion. The level of melatonin and spindle formation have been shown to correlate as we age. Melatonin levels are high until puberty and then start to decline as we age which may be responsible for the decline of spindle formation and increased sleep difficulty in the elderly. Melatonin therapy has been show to enhance spindle activity and can increase the percentage of REM and improve daytime functioning." Much of the research on the pineal gland and how it relates to sleep focuses on changes of the pineal gland and how it can decrease sleep time and quality due to a decrease in melatonin production. One study looked at the pineal gland and sleep from another perspective. It evaluated the effect of early-life sleep deprivation and how it may cause a decrease in pineal gland functioning and reduction in melatonin. This decrease in pineal function then contributed to the development of metabolic dysfunction. Chen found that rats that experienced chronic early sleep deprivation subsequently developed persistent and detrimental effects on pineal signaling and metabolic function, even though the early sleep deprivation insult had already been terminated. This study emphasized the importance of establishing optimal sleep behavior, because early sleep deprivation can have detrimental effects that are persistent throughout life.

The pineal gland, although a small gland, has been shown to influence many functions. The calcification of this gland has often been regarded as part of normal aging, along with the resultant decrease in melatonin production. Kunz, et al stated that "the paradigm of 'physiologic' pineal calcification might need further discussion." Research is showing that several processes including calcium regulation and mast cell activation may be involved in pineal calcification and result in multiple pathologic conditions. Reduction in melatonin production alone has been implicated in insomnia, circadian rhythm disorders, psychologic, and metabolic disorders. Abnormalities in volume and size of the pineal gland may be a due to delays in neurodevelopmental processes and disease such as schizophrenia may develop as a result. It has also been shown that pineal gland development and spindle formation are correlated and patients that have delays in pineal development will also show a delayed appearance of spindles and delayed onset of circadian rhythms and deferred melatonin secretion. A positive correlation and increased risk of stroke, migraine, metabolic syndrome, and schizophrenia, which are all related to pineal function, should motivate practitioners to evaluate their patients more completely when calcifications of the gland are demonstrated on CBCT images.


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