Smaller pineal volume in Alzheimer's disease than in dementia with Lewy bodies

Abstract

Background

Pineal gland volume reduction in Alzheimer's disease (AD) has been reported. Recent findings also indicate an association between pineal volume reduction and dementia with Lewy bodies (DLB).

Objective

This study aimed to compare pineal volume between two major neurodegenerative disorders: AD and DLB.

Methods

This cross-sectional analysis included patients with AD or DLB who underwent brain magnetic resonance imaging (MRI) and Mini-Mental State Examination (MMSE). AD was diagnosed based on the National Institute on Aging-Alzheimer's Association criteria and confirmed by positive amyloid positron emission tomography. DLB was diagnosed per McKeith et al.'s clinical criteria and confirmed by dopamine transporter single-photon emission computed tomography or ¹²³I-metaiodobenzylguanidine myocardial scintigraphy. Pineal parenchymal volume (PPV) was manually measured using MRI data. The Mann–Whitney U test was used for group comparisons, and analysis of covariance (ANCOVA) was performed with logarithmic transformation since PPV was not normally distributed. Covariates included total intracranial volume, age, sex, MMSE score, use of antidementia drugs, use of psychotropic medications, and MRI magnetic field strength.

Results

Seventy-five patients (AD, 41; DLB, 34; 35 women) were analyzed. PPV was significantly smaller in the AD group than in the DLB group (74.7 ± 18.8 versus 96.0 ± 31.6 mm³, U = 1024, p < 0.001). ANCOVA confirmed a significant diagnostic effect (F = 11.9, p < 0.001).

Conclusions

Pineal volume was smaller in AD than in DLB; this difference may reflect the neuropathological characteristics specific to AD.

Keywords

Alzheimer's disease Lewy bodies pineal gland pineal volume reduction

Introduction

Alzheimer's disease (AD), the most common form of dementia, is primarily caused by the accumulation of amyloid-β and phosphorylated tau proteins.¹ Although brain volume loss in AD is typically characterized by atrophy of the hippocampus and parahippocampal gyrus,² several studies have also reported pineal gland volume reduction.^3–5 Pineal volume in AD is smaller than in cognitively normal individuals and in those with mild cognitive impairment (MCI),^3,4 and this reduction appears to occur as early as the MCI stage.⁵ The underlying mechanism of pineal atrophy in AD remains unclear; however, melatonin, which is secreted by the pineal gland, likely plays a role in AD pathophysiology due to its anti-amyloid, anti-tau, and anti-inflammatory properties.^6–8 Previous reviews have demonstrated decreased melatonin concentrations,⁶ including reduced nighttime melatonin levels in both blood and cerebrospinal fluid (CSF), among individuals with AD.⁹ Lower melatonin levels might also be present at the stage of MCI,^6,9,10 although one study observed comparable salivary melatonin levels between the MCI and control groups.¹¹

Dementia with Lewy bodies (DLB) is the second most common form of dementia after AD and is characterized by the pathological accumulation of Lewy bodies, which are abnormal aggregates of alpha-synuclein protein.¹² In Parkinson's disease, another Lewy body disorder, impaired antioxidant activity resulting from decreased melatonin levels may contribute to disease progression, similar to AD.¹³ A previous study reported the relationship between pineal volume reduction and rapid eye movement sleep behavior disorder (RBD) in AD.¹⁴ Because RBD is a core clinical feature of DLB,¹⁵ pineal volume reduction may also be related to RBD in DLB. Moreover, sympathetic denervation secondary to cardiac dysfunction can cause pineal gland dysfunction.¹⁶ As cardiac sympathetic denervation, assessed using ¹²³I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, is a key biomarker in DLB,¹⁵ sympathetic dysfunction in DLB may lead to altered pineal gland function. These findings collectively suggest a possible link between pineal volume reduction and DLB.

Our previous study examined pineal volume in 147 individuals who underwent amyloid positron emission tomography (PET) and dopamine transporter single-photon emission computed tomography (DAT-SPECT).¹⁷ That study demonstrated that amyloid pathology had a stronger association with pineal volume reduction than Lewy body pathology, implying that this phenomenon might be specific to AD. However, only nine individuals in that cohort (seven with AD and two with DLB) had dementia, limiting the generalizability of the findings. To address this gap, the present study examined pineal volume in AD and DLB by comparing pineal volume between patients with AD confirmed by amyloid PET and patients with DLB confirmed by DAT-SPECT or ¹²³I-MIBG myocardial scintigraphy.

Methods

Participants

Patients diagnosed with AD and DLB who underwent brain magnetic resonance imaging (MRI) and Mini-Mental State Examination (MMSE)¹⁸ assessments at Yamagata University Hospital or Oita University Hospital between April 1, 2005, and October 31, 2023, were included in this cross-sectional study. AD was diagnosed on the National Institute on Aging-Alzheimer's Association criteria1 and a visually positive amyloid PET scan. DLB was diagnosed according to the clinical diagnostic criteria of McKeith et al.¹⁵ and confirmed by abnormal findings on DAT-SPECT and/or ¹²³I-MIBG myocardial scintigraphy.

For patients who were actively attending the hospital, written informed consent was obtained from either the patient or a family member. When direct consent could not be obtained, an opt-out procedure was applied. The ethics committees of Yamagata University (2023-245), Oita University (2752-C134), Kyoto Prefectural University of Medicine (ERB-C-3077), and Maizuru Medical Center (R5-28) approved this study.

Pineal parenchymal volume

Pineal parenchymal volume (PPV) was measured manually from brain MRI data using MRIcro software (https://people.cas.sc.edu/rorden/mricro/mricro.html), following previously published protocols (Figure 1).^4,5,17,19 Three-dimensional T1-weighted brain MRI images were acquired at either 1.5 or 3 tesla at Yamagata University Hospital or Oita University Hospital. One author (T.M.) performed all PPV measurements, whereas another author (A.I.) independently measured PPV in 14 randomly selected patients to calculate the inter-rater intraclass correlation coefficient (ICC), consistent with prior studies.^4,5,17,19 The same examiner (T.M.) repeated PPV measurements in 14 patients to determine the intra-rater ICC.

Figure 1.

Example of pineal parenchymal volume measurement. The red-colored area in the lower row indicates the pineal parenchyma. Left column, axial slice; middle column, sagittal slice; right column, coronal slice.

The total intracranial volume (TIV)—defined as the sum of gray matter, white matter, and cerebrospinal fluid volumes—was calculated using Statistical Parametric Mapping 12 (https://www.fil.ion.ucl.ac.uk/spm/software/spm12/).

Statistical analyses

When comparing two groups, the Mann–Whitney U test and chi-squared test were employed. The analysis of covariance (ANCOVA) employed a logarithmic adjustment since the PPV was not normally distributed. Age, sex, TIV, MMSE score, taking antidementia drugs, taking psychotropic drugs, and MRI magnetic field strength were used as covariates in ANCOVA. Since it cannot be ruled out that antidementia drugs and psychotropic medications may affect brain volume, including pineal volume, these variables were used as covariates in the statistical analyses. Multiple regression analysis using the forced-entry method was performed to identify factors associated with PPV. Independent variables included age, sex, TIV, MMSE score, diagnosis, use of antidementia drugs, use of psychotropic medications, and MRI magnetic field strength. All statistical analyses were performed using SPSS version 29 (IBM, Armonk, NY, USA). Statistical significance was set at p < 0.05.

Statistical power was calculated using G*Power 3.1.9.7 (https://www.psychologie.hhu.de/arbeitsgruppen/allgemeine-psychologie-und-arbeitspsychologie/gpower)^20,21 with an α error probability of 0.05.

Results

Participants’ characteristics

A total of 75 patients (AD, 41; DLB, 34; 35 women) were included in this study. The mean and standard deviation of age, MMSE score, PPV, and TIV were 73.2 ± 10.3 years, 19.4 ± 4.9, 84.4 ± 27.4 mm³, and 1505.6 ± 166.2 cm³, respectively. Forty patients used antidementia drugs, including donepezil, galantamine, rivastigmine, and memantine, whereas 24 patients were taking psychotropic medications, 3 of whom used ramelteon. No patient was taking melatonergic supplementation. Brain MRI at 1.5 and 3T was performed in 48 and 27 patients, respectively.

Table 1 summarizes the characteristics of the AD and DLB groups. Significant differences were observed between the two groups in age, PPV, MMSE score, and the use of psychotropic medication.

Table 1.

Participants’ characteristics.

Item	Patients with AD (n = 41)	Patients with DLB (n = 34)	p
Age, years	67.7 ± 9.8	79.8 ± 6.3	<0.001
Sex (male/female)	20/21	20/14	0.385
PPV, mm³	74.7 ± 18.8	96.0 ± 31.6	<0.001
TIV, cm³	1490.9 ± 155.8	1523.3 ± 178.8	0.476
MMSE score	17.9 ± 5.1	21.2 ± 4.0	0.006
Use of antidementia drugs (+/−)	26/15	14/20	0.055
Use of psychotropic medications (+/−)	7/34	17/17	0.002
MRI strength (1.5 T/3.0 T)	27/14	21/13	0.713

Data are presented as numbers or as means ± standard deviations.

AD: Alzheimer's disease; DLB: dementia with Lewy bodies; MMSE: Mini-Mental State Examination; MRI: magnetic resonance imaging; PPV: pineal parenchymal volume; TIV: total intracranial volume.

Comparison of PPV between patients with AD and DLB

The inter-rater and intra-rater ICCs for PPV measurements were 0.710 (95% confidence interval [CI]: 0.308–0.897, p = 0.002) and 0.867 (95% CI: 0.600–0.957, p < 0.001), respectively.

The PPV was significantly smaller in the AD group than in the DLB group (74.7 ± 18.8 versus 96.0 ± 31.6 mm³, U = 1024, p < 0.001) (Figure 2). The effect size (Cohen's d) was 0.84, and the statistical power was 0.937.

Figure 2.

Comparison of pineal parenchymal volume between Alzheimer's disease (AD, n = 41) and dementia with Lewy bodies (DLB, n = 34) groups. The upper row shows box-and-whisker plots for each group. The lower row presents representative examples of pineal parenchymal volume in AD (left column) and DLB (right column) groups.

ANCOVA confirmed a significant effect of diagnosis on PPV (F = 11.9, partial η² = 0.153, p < 0.001). The corresponding effect size (f) was 0.425, with a statistical power of 0.952.

Factors associated with PPV

Multiple regression analysis identified AD diagnosis and TIV as significant predictors of PPV (R² = 0.312, adjusted R² = 0.229, F = 3.747, Durbin–Watson = 1.836, p = 0.001) (Table 2). The effect size (f²) was 0.453, with a statistical power of 0.990.

Table 2.

Results of linear regression analysis.

Variable	B (95% CI)	β	p	VIF
Age	−0.599 (−1.291 to 0.093)	−0.226	0.089	1.635
Male sex	−8.058 (−23.052 to 6.935)	−0.148	0.287	1.823
TIV	0.050 (0.004 to 0.095)	0.302	0.033	1.853
MMSE score	0.461 (−0.892 to 1.814)	0.082	0.499	1.407
AD diagnosis	−23.441 (−39.127 to −7.755)	−0.429	0.004	1.987
Use of antidementia drugs	3.350 (−8.462 to 15.163)	0.061	0.573	1.132
Use of psychotropic medications	11.181 (−2.088 to 24.451)	0.192	0.097	1.249
MRI (3.0T)	−1.912 (−13.940 to 10.115)	−0.034	0.752	1.086

CI: confidence interval; AD: Alzheimer's disease; MMSE: Mini-Mental State Examination; MRI: magnetic resonance imaging; PPV: pineal parenchymal volume; TIV: total intracranial volume; VIF: variance inflation factor.

Discussion

In this study, the pineal volume was significantly smaller in patients with AD (74.7 ± 18.8 mm³) than in patients with DLB (96.0 ± 31.6 mm³). This difference remained significant after adjusting for confounding variables. However, the pineal volume was not compared with that of healthy controls. A previous study reported a mean PPV of 97.7 ± 46.7 mm³ in healthy controls, with the highest Youden index for differentiating AD from controls identified at a PPV cutoff of 66.56 mm.^3,4 Another study found that older individuals with normal cognition had a mean PPV of 116.3 ± 30.8 mm.^3,19 Although these findings are indirect comparisons, they indicate that patients with AD exhibit smaller pineal volumes than cognitively normal individuals, whereas the pineal volume in DLB appears comparable to that in normal cognition.

Although both AD diagnosis and TIV predicted pineal volume in this study, AD diagnosis was the most significant predictor of smaller pineal volume. This finding aligns with previous evidence suggesting that amyloid pathology, rather than Lewy body pathology, is primarily associated with pineal atrophy.¹⁷ Collectively, these results support the idea that between AD and DLB, pineal volume reduction may represent characteristics of AD.

Although smaller pineal volume was not associated with DLB in this study, prior research has indicated potential associations between pineal gland dysfunction and DLB.^13,14,16 Reduced melatonin secretion may contribute to DLB pathogenesis by impairing antioxidant defense mechanisms.¹³ Moreover, sympathetic dysfunction, which affects pineal gland activity, has been implicated in DLB.¹⁶ Therefore, melatonin reduction in DLB may result from sympathetic dysfunction rather than pineal volume reduction. Further research is needed to clarify the interplay between DLB pathology, sympathetic regulation, and melatonin production.

Previous studies have demonstrated associations between pineal volume reduction and age,²² cognitive impairment,⁴ and brain amyloid positivity,¹⁷ whereas other studies have found no significant relationship with age²³ and sex.^4,22–24 In this study, smaller pineal volume was not linked to age or cognitive impairment, although a trend toward an age-related decrease was observed. The pineal volume in AD was smaller than in DLB, although the age in AD was younger than in DLB. Moreover, even after adjustment for age, the pineal volume in AD was smaller than in DLB. Therefore, it seems that the age differences between the AD and DLB groups had little impact on the pineal volume results in this study. Because all participants were patients with dementia and exhibited only mild to moderate cognitive impairment, the severity of cognitive decline may not have influenced pineal volume.

Although AD was associated with a smaller pineal volume, the causal relationship remains unknown. A previous study demonstrated that pineal volume reduction appeared during the MCI stage in individuals who later developed AD.⁵ Moreover, brain amyloid pathology was linked to pineal volume reduction in individuals without dementia.¹⁷ Among the genes associated with pineal gland volume identified through genome-wide association study, MIR206, which encodes the microRNA miR-206, appears particularly relevant due to its links with cognitive decline, MCI, and AD.²⁵ Pineal gland calcification, which is often observed in older people and AD,^3,26 may also contribute to pineal volume reduction.²⁷ An immunocytochemical study did not detect amyloid, tau, or neurofibrillary tangles within the human pineal gland.²⁸ These findings suggest that pineal volume reduction in AD may arise from non-AD pathological mechanisms such as aging, genetic predisposition, or calcification. These factors may contribute to pineal atrophy during the preclinical and prodromal stages of AD. Moreover, CSF melatonin levels decrease in patients with preclinical AD.⁶ Because melatonin exhibits anti-amyloid, anti-tau, and anti-inflammatory properties,^6–8 and pineal volume correlates positively with melatonin concentration,^29–31 a reduction in pineal volume may precede and contribute to diminished melatonin secretion, which in turn could promote AD pathogenesis.

Amyloid peptides act on the pineal gland in rats and inhibit melatonin synthesis by approximately 75%.³² This finding suggests that amyloid deposition in regions of the brain other than the pineal gland may lead to pineal gland dysfunction. The onset of AD may come first, followed by pineal volume reduction. A longitudinal study observing pineal volume from the stage without AD pathology to preclinical AD, MCI due to AD, and AD is required to examine the causal association between pineal volume reduction and AD pathology.

If a smaller pineal volume is associated with AD, elucidating the underlying mechanisms may yield new insights into AD pathophysiology and identify potential therapeutic targets. In this context, melatonin supplementation warrants consideration as a therapeutic strategy. A systematic review demonstrated that melatonin may be more effective for cognitive impairment in MCI and mild AD than disease-modifying drugs for AD, including donanemab, lecanemab, and aducanumab.³³ Another review reported that melatonin could improve cognitive impairment and behavioral and psychiatric symptoms in MCI but not in AD.³⁴ As pineal volume is already reduced at the stage of MCI,⁵ treatment of melatonin may need to be started at the latest by the MCI stage. A randomized controlled trial found relatively high-dose melatonin (25 mg/day) feasible and acceptable for people with MCI; however, no significant differences from placebo were observed in oxidative stress in the brain, sleep, cognitive function, or mood, possibly due to the short observation period (12 weeks).³⁵ A single-arm interventional study demonstrated that a neuroimmune regimen comprised melatonin (100 mg/day), 5-methoxytryptamine (30 mg/day), angiotensin 1-7 (0.5 mg twice daily), and cannabidiol (20 mg twice daily) controlled the cognitive impairment in four out of six patients with AD.³⁶ These findings suggest that melatonin may exert greater therapeutic benefits when administered in combination with other anti-inflammatory agents rather than as a monotherapy.

This study had some limitations. First, the brain MRI field strength varied among the participants; however, the results remained consistent after adjustment for MRI field strength. Second, neuropathologies other than AD and DLB, such as TAR DNA-binding protein 43 kDa pathology and other tauopathies, were not examined. Nonetheless, a major strength of this study was the inclusion of participants whose diagnoses were confirmed by amyloid PET and suggestive biomarkers for DLB. Third, a comparison with a healthy control group was not performed. Fourth, only pineal volume was evaluated, without direct measurement of melatonin levels, which could provide additional insight into pineal gland function. Fifth, the AD group was younger than the DLB group, and the two groups also differed in MMSE score and use of psychotropic medications. Although these variables were adjusted for in the analyses, residual confounding cannot be completely excluded. Sixth, because the pineal gland is a small structure, volumetric measurements may be subjected to variability and limitations in accuracy. Moreover, pineal volume might be influenced by factors such as circadian rhythms, sleep duration, light exposure, and calcification. Further research addressing these limitations is warranted.

In conclusion, patients with AD exhibited significantly smaller pineal volumes than those with DLB. A smaller pineal volume may reflect the neuropathological characteristics specific to AD.

Footnotes

Acknowledgements

The manuscript has been proofread by a professional, native English-speaking editor (Editage).

ORCID iDs

Teruyuki Matsuoka

Teruaki Masuda

Takuya Ataka

Jin Narumoto

Ethical considerations

The ethics committees of Yamagata University (2023-245), Oita University (2752-C134), Kyoto Prefectural University of Medicine (ERB-C-3077), and Maizuru Medical Center (R5-28) approved this study.

Consent to participate

Written informed consent was obtained from the patient or a family member. For cases in which consent could not be obtained, an opt-out procedure was implemented.

Consent for publication

Not applicable.

Author contribution(s)

Teruyuki Matsuoka: Conceptualization; Formal analysis; Methodology; Writing – original draft.

Ryota Kobayashi: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Writing – review & editing.

Ayu Imai: Methodology; Writing – review & editing.

Kazutaka Sakamoto: Data curation; Investigation; Writing – review & editing.

Daichi Morioka: Data curation; Investigation; Writing – review & editing.

Akihito Suzuki: Methodology; Supervision; Writing – review & editing.

Noriyuki Kimura: Conceptualization; Data curation; Investigation; Methodology; Project administration; Supervision; Writing – review & editing.

Teruaki Masuda: Data curation; Investigation; Writing – review & editing.

Takuya Ataka: Data curation; Investigation; Writing – review & editing.

Jin Narumoto: Methodology; Supervision; Writing – review & editing.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a Grant-in-Aid from the Ministry of Health, Labour and Welfare through its Research on Dementia program (Grant Number: 23GB1003).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The raw data used in this study include sensitive and personally identifiable information, such as age and sex, which could compromise participant privacy. The data that support the findings of this study are available upon approval from the local ethics committees of Yamagata University and Oita University. Requests for access should be directed to the corresponding author.

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