Pineal Calcification
Pineal gland calcification (PGC) occurs when deposits form on the pineal gland, primarily consisting of calcium and phosphorus, but also magnesium and strontium (1–3). PGC is reported to occur from fetal life to adulthood, though it increases in prevalence with aging (3,4).
Two types of PGC:
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Intra-pineal calcification: located in the parenchyma; sometimes referred to as ‘brain sand’, composed of mostly calcium and magnesium, found mostly in adults and aging patients (3,5)
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Extra-pineal calcification: located in the capsule of the gland; common among the older population (3)
The development of PGC has been conflicting, as some studies report PGC can be physiological (asymptomatic, not accompanying disease or age) or pathological (caused by disease or other abnormalities and increases with the aging process) (3,4). However, research in more recent times has strongly suggested that PGC is associated with aging and pathological disorders, such as neurodegenerative diseases (NDDs) (4). The increased prevalence of PGC in the aging population also supports that this is more than just a physiological process (4). The prevalence of PGC in the aging population is reported from 28.66 to 76.7%, with variability in the findings based on gender and country of origin. One meta-analysis reported a pooled prevalence of 61.65%, with the highest prevalence in India and the lowest in Iraq (3).
The ‘gold standard’ for diagnosing PGC is completed post-mortem taking a biopsy of the brain, making a comprehensive assessment and clinical utility a challenge (2). However, researchers are using various testing methods, such as CT scans and MRIs to assess PGC.
Relationship between melatonin and PGC
PGC leads to decreased melatonin production, reduced pineal volume size, and altered sleep patterns (1,5), though it is also a contributing risk factor of NDDs, particularly Alzheimer’s disease and multiple sclerosis (2,4), migraines (6), symptomatic intracerebral hemorrhage (7), symptomatic cerebral infarction (8), and pediatric primary brain tumor (9). In Alzheimer’s disease, both pineal calcification and reduced pineal gland size have been reported in this population (1). In one study, migraine sufferers had significantly higher PGC than placebo, independent of age (6). Another study found a positive association between PGC and degenerative disc disease (10). Further, abnormalities in sleep, including insomnia, and circadian rhythm disorders, may be partly related to decreased pineal gland volume or pineal calcification, resulting in reduced melatonin production (1). Del Brutto, et al. called PGC a “surrogate for melatonin deficiency” (11).
One of melatonin’s functions is to provide protection to the mitochondria by acting as a powerful antioxidant and free radical scavenger. By preventing damage caused by reactive oxygen species (ROS), the mitochondria can increase the production of energy (ATP) (12) and therefore protect the mitochondrial membrane from collapsing. This mechanism further prevents calcium influx inhibits membrane permeability and reduces cell death (13). Not only does an influx of calcium can damage cells, but PGC is primarily composed of calcium deposits.
Image Credit: Song J. Pineal gland dysfunction in Alzheimer's disease: relationship with the immune-pineal axis, sleep disturbance, and neurogenesis. Mol Neurodegener. 2019;14(1):28. Published 2019 Jul 11. doi:10.1186/s13024-019-0330-8. (http://creativecommons.org/licenses/by/4.0/)
Contributors to PGC
The most common genetic and environmental factors that contribute to PGC include the male gender (3,14), those living in a low altitude, and low sunlight exposure (3). However, some lifestyle factors, such as smoking, cell phone use/electric and magnetic field exposure, nutrition (2–4), fluoride intake (15), and herbicide exposure (3), have also been explored. Tan, et al. have reported that chronic vascular inflammation, brain tissue hypoxia, and intracranial pressure may contribute to PGC, though this is speculative at present (4).
A cross-sectional analysis of 586 patients utilized CT scans to assess pineal calcification. Researchers found male sex (P<0.001) and smoking cigarettes (p=0.001) to be the highest risk factors for PGC (2). Of note, 84.47% of the participants in this study were reported to have PGC (2). While studies are limited, existing literature suggests that men with low melatonin levels (measured by urinary 6- sulfatoxymelatonin), high parenchyma volume, pineal cysts, and pineal calcification almost twice the risk of total prostate cancer (16).
Brain Function and PGC
Another study of 237 participants explored pineal parenchymal volume (PPV) utilizing MRI. The aim was to assess if the PPV in individuals with mild cognitive impairment (MCI) would correlate to the conversion to Alzheimer’s Disease (AD). PPV was found to be substantially reduced in those who had MCI and went on to develop AD. In this study, 29% of participants developed AD within 41 months, though conversion rates in other studies ranged from 23 to 68% in 13-60 months. Pineal volume, cognitive function, and cerebral spinal fluid (CSF) amyloid beta peptide (Ab1-42) all show to be significant predictors in the conversion from MCI to AD. Patients with low PPV also had low CSF Ab1-42 and high CSF p-tau181, markers that can be used in the diagnosis of dementia and Alzheimer’s disease. Pineal calcification was not explored in this study due to the testing methods utilized (MRI) (17).
Conclusion
In summary, it is hypothesized by many authors that pineal calcification may cause a melatonin deficit, while others suggest that the decrease in melatonin, which naturally occurs with age, may be a reason why pineal calcification is more prevalent as individuals age.
As melatonin has been shown to provide benefits for a variety of conditions, including circadian rhythm disorders, sleep, cognitive health, cancer prevention, migraines, and overall healthy aging, it may be reasonable to utilize melatonin therapy for PGC; however, at present, human trials and doses of melatonin specific for PGC have not been established in the literature.
Written by: Kim Ross, DCN
Reviewed by Deanna Minich, PhD
March 21, 2023
References
1. Song J. Pineal gland dysfunction in Alzheimer’s disease: Relationship with the immune-pineal axis, sleep disturbance, and neurogenesis. Vol. 14, Molecular Neurodegeneration. 2019.
2. Jalali N, Firouzabadi MD, Mirshekar A, Khalili P, Ravangard A reza, Ahmadi J, et al. Cross-sectional analysis of potential risk factors of the pineal gland calcification. BMC Endocr Disord. 2023 Feb 28;23(1):49.
3. Belay DG, Worku MG. Prevalence of pineal gland calcification: systematic review and meta-analysis. Syst Rev. 2023 Mar 6;12(1):32.
4. Tan D, Xu B, Zhou X, Reiter R. Pineal Calcification, Melatonin Production, Aging, Associated Health Consequences and Rejuvenation of the Pineal Gland. Molecules. 2018 Jan 31;23(2):301.
5. Beker-Acay M, Turamanlar O, Horata E, Unlu E, Fidan N, Oruc S. Assessment of Pineal Gland Volume and Calcification in Healthy Subjects: Is it Related to Aging? J Belg Soc Radiol. 2016 Feb 1;100(1).
6. Ozlece HK, Akyuz O, Ilik F, Huseyinoglu N, Aydin S, Can S, et al. Is there a correlation between the pineal gland calcification and migraine? Eur Rev Med Pharmacol Sci. 2015 Oct;19(20):3861–4.
7. Kitkhuandee A, Sawanyawisuth K, Johns J, Kanpittaya J, Tuntapakul S, Johns NP. Pineal calcification is a novel risk factor for symptomatic intracerebral hemorrhage. Clin Neurol Neurosurg. 2014 Jun;121:51–4.
8. Kitkhuandee A, Sawanyawisuth K, Johns NP, Kanpittaya J, Johns J. Pineal Calcification Is Associated with Symptomatic Cerebral Infarction. Journal of Stroke and Cerebrovascular Diseases. 2014 Feb;23(2):249–53.
9. Tuntapakul S, Kitkhuandee A, Kanpittaya J, Johns J, Johns NP. Pineal calcification is associated with pediatric primary brain tumor. Asia Pac J Clin Oncol. 2016 Dec;12(4):e405–1
10. Turgut AT, Sönmez I, Çakıt BD, Koşar P, Koşar U. Pineal gland calcification, lumbar intervertebral disc degeneration and abdominal aorta calcifying atherosclerosis correlate in low back pain subjects: A cross-sectional observational CT study. Pathophysiology. 2008 Jun;15(1):31–9.
11. Del Brutto OH, Mera RM, Castle P, Kiernan J, Del Brutto VJ, Recalde BY, et al. The association between pineal gland calcification and white matter hyperintensities of presumed vascular origin in older adults. A population-based study. Journal of Clinical Neuroscience. 2020 Feb;72:202–5.
12. Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Melatonin in mitochondrial dysfunction and related disorders. International Journal of Alzheimer’s Disease. 2011.
13. Kopustinskiene DM, Bernatoniene J. Molecular mechanisms of melatonin-mediated cell protection and signaling in health and disease. Pharmaceutics. 2021.
14. Mohammed KA, Adjei Boakye E, Ismail HA, Geneus CJ, Tobo BB, Buchanan PM, et al. Pineal Gland Calcification in Kurdistan: A Cross-Sectional Study of 480 Roentgenograms. PLoS One. 2016 Jul 14;11(7):e0159239.
15. Nakamoto T, Rawls HR. Fluoride Exposure in Early Life as the Possible Root Cause of Disease In Later Life. Journal of Clinical Pediatric Dentistry. 2018 Jan 1;42(5):325–30.
16. Bazzi LA, Sigurdardottir LG, Sigurdsson S, Valdimarsdottir U, Torfadottir J, Aspelund T, et al. Exploratory assessment of pineal gland volume, composition, and urinary 6‐sulfatoxymelatonin levels on prostate cancer risk. Prostate. 2021 Jun 16;81(8):487–96.
17. Matsuoka T, Oya N, Yokota H, Akazawa K, Yamada K, Narumoto J. Pineal volume reduction in patients with mild cognitive impairment who converted to Alzheimer’s disease. Psychiatry Clin Neurosci. 2020;74(11).