Brain glymphatic dysfunction is critical in neurodegenerative processes. While animal studies have provided substantial insights, understandings in humans remains limited. Recent attention has focused on the non-invasive evaluation of brain glymphatic function. However, its association with brain parenchymal lesions in large-scale population remains under-investigated. In this cross-sectional analysis of 1030 participants (57.14 ± 9.34 years, 37.18% males) from the Shunyi cohort, we developed an automated pipeline to calculate diffusion-weighted image analysis along the perivascular space (ALPS), with a lower ALPS value indicating worse glymphatic function. The automated ALPS showed high consistency with the manual calculation of this index (ICC = 0.81, 95% CI: 0.662-0.898). We found that those with older age and male sex had lower automated ALPS values (β = -0.051, SE = 0.004, p < .001, per 10 years, and β = -0.036, SE = 0.008, p < .001, respectively). White matter hyperintensity (β = -2.458, SE = 0.175, p < .001) and presence of lacunes (OR = 0.004, 95% CI < 0.002-0.016, p < .001) were significantly correlated with decreased ALPS. The brain parenchymal and hippocampal fractions were significantly associated with decreased ALPS (β = 0.067, SE = 0.007, p < .001 and β = 0.040, SE = 0.014, p = .006, respectively) independent of white matter hyperintensity. Our research implies that the automated ALPS index is potentially a valuable imaging marker for the glymphatic system, deepening our understanding of glymphatic dysfunction.

UNASSIGNED: We aimed to use the onset time of Alzheimer\'s disease (AD) as the reference time to longitudinally investigate the atrophic characteristics of brain structures prior to the onset of AD.
UNASSIGNED: A total of 328 participants from the ADNI database with clear onset of AD and structural imaging data were included in our study. The time before the onset of AD (abbreviated as BAD) was calculated. We investigated the longitudinal brain changes in 97 regions using multivariate linear mixed effects regression models.
UNASSIGNED: The average BAD was -28.15 months, with a range from -156 to 0 months. The 54 brain regions showed significant atrophy prior to the onset of AD, and these regions were mainly distributed in the frontal and temporal lobes. The parietal and occipital lobe exhibited relatively less atrophy than the other brain lobes. Sex, age, and magnetic field strength had greater direct impacts on structural indicators than APOE genotype and education. The analysis of interaction effects revealed that the APOE ε4 mutation carriers exhibited more severe structural changes in specific brain regions as the BAD increased. However, sex, age, and education had minimal regulatory influence on the structural changes associated with BAD.
UNASSIGNED: Longitudinal analysis, with the onset time point of AD as the reference, can accurately describe the features of structural changes preceding the onset of AD and provide a comprehensive understanding of AD development.

BACKGROUND: Migraine is a neurological disease with a significant genetic component and is characterized by recurrent and prolonged episodes of headache. Previous epidemiological studies have reported a higher risk of dementia in migraine patients. Neuroimaging studies have also shown structural brain atrophy in regions that are common to migraine and dementia. However, these studies are observational and cannot establish causality. The present study aims to explore the genetic causal relationship between migraine and dementia, as well as the mediation roles of brain structural changes in this association using Mendelian randomization (MR).
METHODS: We collected the genome-wide association study (GWAS) summary statistics of migraine and its two subtypes, as well as four common types of dementia, including Alzheimer\'s disease (AD), vascular dementia, frontotemporal dementia, and Lewy body dementia. In addition, we collected the GWAS summary statistics of seven longitudinal brain measures that characterize brain structural alterations with age. Using these GWAS, we performed Two-sample MR analyses to investigate the causal effects of migraine and its two subtypes on dementia and brain structural changes. To explore the possible mediation of brain structural changes between migraine and dementia, we conducted a two-step MR mediation analysis.
RESULTS: The MR analysis demonstrated a significant association between genetically predicted migraine and an increased risk of AD (OR = 1.097, 95% CI = [1.040, 1.158], p = 7.03 × 10- 4). Moreover, migraine significantly accelerated annual atrophy of the total cortical surface area (-65.588 cm2 per year, 95% CI = [-103.112, -28.064], p = 6.13 × 10- 4) and thalamic volume (-9.507 cm3 per year, 95% CI = [-15.512, -3.502], p = 1.91 × 10- 3). The migraine without aura (MO) subtype increased the risk of AD (OR = 1.091, 95% CI = [1.059, 1.123], p = 6.95 × 10- 9) and accelerated annual atrophy of the total cortical surface area (-31.401 cm2 per year, 95% CI = [-43.990, -18.811], p = 1.02 × 10- 6). The two-step MR mediation analysis revealed that thalamic atrophy partly mediated the causal effect of migraine on AD, accounting for 28.2% of the total effect.
CONCLUSIONS: This comprehensive MR study provided genetic evidence for the causal effect of migraine on AD and identified longitudinal thalamic atrophy as a potential mediator in this association. These findings may inform brain intervention targets to prevent AD risk in migraine patients.

The current study aimed to evaluate the susceptibility to regional brain atrophy and its biological mechanism in Alzheimer\'s disease (AD). We conducted data-driven meta-analyses to combine 3,118 structural magnetic resonance images from three datasets to obtain robust atrophy patterns. Then we introduced a set of radiogenomic analyses to investigate the biological basis of the atrophy patterns in AD. Our results showed that the hippocampus and amygdala exhibit the most severe atrophy, followed by the temporal, frontal, and occipital lobes in mild cognitive impairment (MCI) and AD. The extent of atrophy in MCI was less severe than that in AD. A series of biological processes related to the glutamate signaling pathway, cellular stress response, and synapse structure and function were investigated through gene set enrichment analysis. Our study contributes to understanding the manifestations of atrophy and a deeper understanding of the pathophysiological processes that contribute to atrophy, providing new insight for further clinical research on AD.

Diabetic cognitive impairment is a common complication in type 2 diabetes. Berberine (BBR) is an isoquinoline alkaloid that has been shown to have neuroprotective effects against diabetes. This study aimed to investigate the effect of BBR on the gray and white matter of the brain by using magnetic resonance imaging (MRI) and to explore the underlying mechanisms. The study used diabetic db/db mice and administered BBR (50 and 100 mg/kg) intragastrically for twelve weeks. Morris water maze was applied to examine cognitive function. T2-weighted imaging (T2WI) was performed to assess brain atrophy, and diffusion tensor imaging (DTI) combined with fiber tracking was conducted to monitor the structural integrity of the white matter, followed by histological immunostaining. Furthermore, the protein expressions of the phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)/ glycogen synthase kinase-3β (GSK-3β) were detected. The results revealed that BBR significantly improved the spatial learning and memory of the db/db mice. T2WI exhibited ameliorated brain atrophy in the BBR-treated db/db mice, as evidenced by reduced ventricular volume accompanied by increased hippocampal volumes. DTI combined with fiber tracking revealed that BBR increased FA, fiber density and length in the corpus callosum/external capsule of the db/db mice. These imaging findings were confirmed by histological immunostaining. Notably, BBR significantly enhanced the protein levels of phosphorylated AKT at Ser473 and GSK-3β at Ser9. Collectively, this study demonstrated that BBR significantly improved the cognitive function of the diabetic db/db mice through ameliorating brain atrophy and promoting white matter reorganization via AKT/GSK-3β pathway.

BACKGROUND: This study aims to investigate the temporal and spatial patterns of structural brain injury related to deep medullary veins (DMVs) damage.
RESULTS: This is a longitudinal analysis of the population-based Shunyi cohort study. Baseline DMVs numbers were identified on susceptibility-weighted imaging. We assessed vertex-wise cortex maps and diffusion maps at both baseline and follow-up using FSL software and the longitudinal FreeSurfer analysis suite. We performed statistical analysis of global measurements and voxel/vertex-wise analysis to explore the relationship between DMVs number and brain structural measurements. A total of 977 participants were included in the baseline, of whom 544 completed the follow-up magnetic resonance imaging (age 54.97±7.83 years, 32% men, mean interval 5.56±0.47 years). A lower number of DMVs was associated with a faster disruption of white matter microstructural integrity, presented by increased mean diffusivity and radial diffusion (β=0.0001 and SE=0.0001 for both, P=0.04 and 0.03, respectively), in extensive deep white matter (threshold-free cluster enhancement P<0.05, adjusted for age and sex). Of particular interest, we found a bidirectional trend association between DMVs number and change in brain volumes. Specifically, participants with mild DMVs disruption showed greater cortical enlargement, whereas those with severe disruption exhibited more significant brain atrophy, primarily involving clusters in the frontal and parietal lobes (multiple comparison corrected P<0.05, adjusted for age, sex, and total intracranial volume).
CONCLUSIONS: Our findings posed the dynamic pattern of brain parenchymal lesions related to DMVs injury, shedding light on the interactions and chronological roles of various pathological mechanisms.

BACKGROUND: Observational studies have explored the relationships of periodontitis with brain atrophy and cognitive impairment, but these findings are limited by reverse causation, confounders and have reported conflicting results. Our study aimed to investigate the causal associations of periodontitis with brain atrophy and cognitive impairment through a comprehensive bidirectional Mendelian randomization (MR) research.
METHODS: We incorporated two distinct genome-wide association study (GWAS) summary datasets as an exploration cohort and a replication cohort for periodontitis. Four and eight metrics were selected for the insightful evaluation of brain atrophy and cognitive impairment, respectively. The former involved cortical thickness and surface area, left and right hippocampal volumes, with the latter covering assessments of cognitive performance, fluid intelligence scores, prospective memory, and reaction time for mild cognitive impairment to Alzheimer\'s disease (AD), Lewy body dementia, vascular dementia and frontotemporal dementia for severe situations. Furthermore, supplementary analyses were conducted to examine the associations between the longitudinal rates of change in brain atrophy and cognitive function metrics with periodontitis. The main analysis utilized the inverse variance weighting (IVW) method and evaluated the robustness of the results through a series of sensitivity analyses. For multiple tests, associations with p-values < 0.0021 were considered statistically significant, while p-values ≥ 0.0021 and < 0.05 were regarded as suggestive of significance.
RESULTS: In the exploration cohort, forward and reverse MR results revealed no causal associations between periodontitis and brain atrophy or cognitive impairment, and only a potential causal association was found between AD and periodontitis (IVW: OR = 0.917, 95% CI from 0.845 to 0.995, P = 0.038). Results from the replication cohort similarly corroborated the absence of a causal relationship. In the supplementary analyses, the longitudinal rates of change in brain atrophy and cognitive function were also not found to have causal relationships with periodontitis.
CONCLUSIONS: The MR analyses indicated a lack of substantial evidence for a causal connection between periodontitis and both brain atrophy and cognitive impairment.

This mediation analysis aimed to investigate the associations among areal bone mineral density, mobility-related brain atrophy, and specific gait patterns. A total of 595 participants from the Taizhou Imaging Study, who underwent both gait and bone mineral density measurements, were included in this cross-sectional analysis. We used a wearable gait tracking device to collect quantitative gait parameters and then summarized them into independent gait domains with factor analysis. Bone mineral density was measured in the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry. Magnetic resonance images were obtained on a 3.0-Tesla scanner, and the volumes of brain regions related to mobility were computed using FreeSurfer. Lower bone mineral density was found to be associated with higher gait variability, especially at the site of the lumbar spine (β = 0.174, FDR = 0.001). Besides, higher gait variability was correlated with mobility-related brain atrophy, like the primary motor cortex (β = 0.147, FDR = 0.006), sensorimotor cortex (β = 0.153, FDR = 0.006), and entorhinal cortex (β = 0.106, FDR = 0.043). Bidirectional mediation analysis revealed that regional brain atrophy contributed to higher gait variability through the low lumbar spine bone mineral density (for the primary motor cortex, P = 0.018; for the sensorimotor cortex, P = 0.010) and the low lumbar spine bone mineral density contributed to higher gait variability through the primary motor and sensorimotor cortices (P = 0.026 and 0.010, respectively).

Observational studies link elevated plasma homocysteine (Hcy) with vascular disease. Our aim was to assess the gender difference in the association between the plasma tHcy level and brain atrophy and identify the possible influencer. We employed Mendelian randomization (MR) to explore the causal relationship between plasma tHcy level, estradiol level, and brain atrophy.
A total of 687 patients with brain atrophy were included, and gender-specific subgroup analyses in association between tHcy and brain atrophy are conducted. From genome-wide association studies, we selected genetic variants (P < 5 × 10-8) for the plasma tHcy level and estradiol level. We investigated the degree of brain atrophy (including gray matter volume and total brain volume) in the UK biobank (n = 7,916). The inverse variance-weighted and several sensitivity MR regression analyses were carried out.
The plasma tHcy level was significantly associated with brain atrophy for females, but not for males. An MR study showed that there was little evidence of the causal link between elevated plasma tHcy and brain atrophy. On the other hand, we found evidence to support causality for genetically decreased estradiol with higher risk of brain atrophy. Furthermore, genetic predisposition to elevated plasma tHcy was associated with a lower estradiol level.
The influence of estradiol on the association between tHcy and brain atrophy deserves further investigation.

BACKGROUND: The association of dietary patterns and longitudinal changes in brain volume has rarely been investigated in Japanese individuals. We prospectively investigated this association in middle-aged and older Japanese community-dwelling adults.
METHODS: Data with a 2-year follow-up from the sixth wave (July 2008 to July 2010; baseline) to the seventh (July 2010 to July 2012; follow-up) of the National Institute for Longevity Sciences-Longitudinal Study of Aging project were analyzed. Dietary intake was assessed using a 3-day dietary record, and longitudinal volume changes (%) in the total gray matter (TGM), total white matter, and frontal, parietal, occipital, temporal, and insular lobes were assessed using 3-dimensional T1 magnetic resonance imaging scans. Multiple factor analysis and hierarchical clustering revealed sex-specific dietary patterns. Associations between dietary patterns and annual brain-volume changes (%) were evaluated using general linear models adjusted for age, apoprotein E genotype, body mass index, medical history, lifestyle behaviors, socioeconomic factors, and energy intake.
RESULTS: Among the 1636 participants (age: 40.3-89.2 years), three dietary patterns were determined for men (n = 815; Western; Vegetable-Fruit-Dairy; and Traditional Japanese diets) and women (n = 821; Western; Grain-Vegetable-Fruit; and Traditional Japanese diets). Compared to women following the Western diet, those on the Traditional Japanese diet had less TGM atrophy. Multivariable-adjusted β (95% confidence interval) of the annual change (%) of TGM was - 0.145 (-0.287 to -0.002; P = 0.047), which correlated with reduced parietal lobe atrophy. No association between dietary pattern and brain atrophy was observed in men.
CONCLUSIONS: Adherence to healthy dietary patterns, with higher consumption of whole grains, seafood, vegetables, fruits, mushrooms, soybean products, and green tea, potentially confers a protective effect against brain atrophy in middle-aged and older Japanese women but not in men. Further research to confirm these results and ascertain the underlying mechanisms is required. This study highlights the importance of sex-specific effects on the relationship between dietary patterns and brain health in diverse populations.