Search Results (181)

Background/Objectives: Frank’s sign, a diagonal earlobe crease, may reflect systemic microvascular dysfunction. We investigated whether Frank’s sign serves as a clinical marker of white matter hyperintensity (WMH) burden in Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), a monogenic model of pure cerebral small vessel disease. Methods: We analyzed 81 genetically confirmed CADASIL patients (61.8 ± 12.6 years, 40.7% female) and 54 age/sex-matched controls (70.3 ± 6.6 years, 48.1% female). Frank’s sign was detected using deep learning from brain MRI-reconstructed 3D facial surfaces. WMH volumes were automatically quantified and adjusted for confounders using Random Forest regression residuals. We compared Frank’s sign prevalence between groups, assessed within-CADASIL associations, and evaluated dose–response relationships across WMH tertiles. Results: Frank’s sign prevalence was significantly higher in CADASIL versus controls (66.7% vs. 42.6%, p = 0.020), with strengthened association after multivariate adjustment (OR = 4.214, 95% CI: 1.128–15.733, p = 0.032). Within CADASIL, Frank’s sign-positive patients showed 72% greater WMH burden (51.5 ± 27.1 vs. 30.0 ± 26.1 mL, p < 0.001) and lower Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) total scores (57.7 ± 19.6 vs. 71.2 ± 22.8, p = 0.006), but similar lacunes, microbleeds, and hippocampal volumes. A robust dose–response relationship emerged across WMH tertiles, with Frank’s sign prevalence increasing from 37.0% (lowest) to 74.1% (highest tertile; adjusted OR = 3.571, 95% CI: 1.134–11.253, p = 0.030). Conclusions: Frank’s sign represents an accessible biomarker of WMH burden in CADASIL, demonstrating disease-specificity and dose–response characteristics independent of vascular risk factors. The automated MRI-based detection method of Frank’s sign enables retrospective analysis of existing neuroimaging databases, transforming a bedside observation into a quantifiable neuroimaging biomarker for genetic small vessel disease stratification. Full article

Autopsy studies have shown that Alzheimer’s disease (AD) often coexists with cerebrovascular injury, affecting cognitive outcomes and the effectiveness of anti-amyloid-beta (Aβ) drugs. No fluid biomarkers of cerebrovascular injury have been identified yet. We investigated the association between white matter hyperintensities (WMH) severity and fluid biomarkers, including cerebrospinal fluid (CSF) neurofilament light chain and plasma placental growth factor (PlGF) levels. This study included 242 patients from memory clinics. Magnetic resonance imaging (MRI), CSF, and plasma samples were collected. Patients were classified as AD+ or non-AD based on the CSF Aβ42/Aβ40 ratio. In the discovery cohort (79 AD+ and 20 non-AD patients with 3D-T1 images), we analyzed the association between WMH volume and plasma PlGF. In the validation cohort (54 AD+ patients without 3D-T1 images), we analyzed the association between WMH grading and plasma PlGF. Among AD+ patients in the discovery cohort, plasma PlGF levels remained significantly associated with WMH volume and grading after adjusting for age, sex, and global cognition. Among the AD+ patients in the validation cohort, the high-PlGF (above median) group had significantly greater WMH volumes and a higher number of patients with a high WMH grading than the low-PlGF (below median) group. Plasma PlGF is a promising marker of cerebrovascular injury in AD. Full article

Objective: Oral frailty is associated with an increased risk of cognitive decline, yet practical tools for early identification remain limited. The Oral Frailty 5-item Checklist (OF-5), recently standardized in Japan, does not account for severe tooth loss, which is a known risk factor for brain atrophy. We developed a revised version of the OF-5 that includes the criterion of having nine or fewer teeth. This study aimed to validate the revised OF-5 as a screening tool for detecting early brain structural changes related to dementia risk in cognitively unimpaired older adults. Methods: We analyzed 732 cognitively unimpaired participants from a population-based Japanese cohort (baseline 2016–2018). Oral frailty was assessed using both the original OF-5 and the revised OF-5. Brain volumes were measured by MRI and processed with FreeSurfer. Associations between oral frailty status and regional brain volumes were tested using multivariable-adjusted models, with further adjustment for nutrient intake and food consumption. Results: The revised OF-5, which adds severe tooth loss (≥9 teeth) as a criterion, showed greater sensitivity in detecting dementia-related brain changes than the original version. With the original OF-5, oral frailty was associated only with reduced fusiform gyrus volume (1.088% vs. 1.109% of estimated total intracranial volume [eTIV]; p < 0.05). In contrast, the revised OF-5 detected broader changes: orally frail participants showed significantly higher white matter hyperintensity (WMH) volume (0.366% vs. 0.302% of eTIV; p < 0.05) and smaller volumes in the medial temporal lobe (1.824% vs. 1.856%), pars triangularis (0.401% vs. 0.412%), and fusiform gyrus (1.080% vs. 1.111%)—all p < 0.05 (FWE-corrected). These associations persisted after adjusting for nutrient intake and food consumption. Conclusions: The revised OF-5 improves identification of pre-symptomatic brain changes in cognitively healthy older adults, independent of nutrition. It may serve as a simple and practical tool for early screening of dementia risk in clinical and community settings. Full article

Cerebral amyloid angiopathy (CAA) is an increasingly recognized cause of cognitive decline and lobar intracerebral hemorrhage in older adults. Recent research highlights that neuropsychiatric symptoms (NPSs)—including depression, anxiety, apathy, and irritability—are highly prevalent in CAA, often emerging prior to overt cognitive impairment or major vascular events. Compared to other cerebrovascular diseases, CAA presents a distinctive and multifaceted NPS profile, with symptoms closely linked to disease severity and neuroimaging biomarkers such as white matter hyperintensities and microbleeds. Critically, NPSs in CAA can complicate cognitive assessment and predict worse functional outcomes, yet remain underappreciated in clinical and research contexts. Management is complicated by pharmacologic risks—including heightened bleeding risk associated with SSRIs and novel anti-amyloid therapies—underscoring the need for individualized and multidisciplinary approaches. We highlight the urgent need for standardized NPS assessment, targeted research into mechanisms and treatment, and greater integration of neuropsychiatric evaluation into CAA care. We suggest that recognizing NPSs as core clinical features—not secondary complications—of CAA is essential to improving both patient outcomes and scientific understanding. Future studies should focus on longitudinal analyses, the development of tailored interventions, and robust comparative research to clarify the pathophysiology, clinical trajectory, and optimal management of NPSs in CAA. Full article

Background and Objectives: The objective of this research is to make a comparative evaluation of the correlation between the volumetric examination of subcortical cerebral regions and white matter hyperintensities classified according to the Fazekas scoring system. Materials and Methods: A total of 236 cases with cranial MRI studies were retrospectively analyzed. This study included patients aged over 45 years who had white matter hyperintensities and who did not have a prior stroke diagnosis. White matter hyperintensities were evaluated in axial FLAIR images according to Fazekas’s grading scale. Patients with Fazekas 0 and 1 were grouped in group 1 and the patients with Fazekas 2 and 3 were grouped in group 2. MRI data processing and subcortical volumetric analyses were performed using the volBrain MRI brain volumetry system. Results: There were statistically significant differences between groups 1 and 2 in terms of cerebrospinal fluid total brain white and gray matter (p < 0.001), total brain white and gray matter (p = 0.009), total cerebrum (p < 0.001), accumbens (p < 0.001), thalamus (p < 0.001), frontal lobe (p < 0.001), parietal lobe (p < 0.001), and lateral ventricle (p < 0.001) volumes. Conclusions: Our study finds a strong link between white matter hyperintensity burden and brain atrophy. This includes volume reductions in total brain white and gray matter, frontal and parietal lobe atrophy, increased cerebrospinal fluid (CSF), and atrophy in specific brain regions such as the accumbens and thalamus. Full article

Background/Objectives: Cardiovascular disease (CVD) contributes to stroke and dementia. Individuals with CVD have high risk for adverse cognitive outcomes and stroke, possibly due to shared risk factors between CVD, stroke, and dementia, which may be attributed to cerebral small vessel disease (CSVD). We aim to determine the association between prevalent CVD and atrial fibrillation (AF) with CSVD. Methods: Composite of CVD [coronary heart disease, heart failure (HF)], its individual components, and AF were assessed. Multi-marker CSVD score was used to reflect increasing CSVD burden (cerebral microbleeds (CMBs), high-burden perivascular spaces, extensive white matter hyperintensity, cortical superficial siderosis, or covert brain infarcts were assigned 1 point each, with a range of 0–5). We related prevalent CVD, its individual components, and AF to multi-marker CSVD score and individual CSVD markers using logistic regression analyses adjusted for age, sex, FHS cohort, time between MRI and clinic exam (model-1), and vascular risk factors (model-2). Results: In 3413 participants (mean age: 59 ± 14 years, 53.4% women), 11% had prevalent CVD or AF, 8% had prevalent CVD, and 4% had prevalent AF. One CSVD marker was seen in 23% participants, and 9% had ≥ 2 markers. In multivariable-adjusted analyses, composite prevalent CVD and AF was associated with the presence of one CSVD marker (OR: 1.38, 95% confidence interval [CI]: 1.05–1.84). The association with ≥2 CSVD markers was not significant. Only CMBs were associated with components of CVD and AF, with the highest odds of association with HF. Conclusions: Prevalent CVD (including AF) is associated with the presence of CSVD, with all components associated with CMBs. Full article

Background: Vascular risk factors (VRFs) are known to influence cerebral small vessel disease (cSVD) burden and progression. However, their specific impact on the presence and distribution of each cSVD imaging marker (white matter hyperintensity [WMH], perivascular spaces [PVSs], lacunes, and cerebral microbleeds [CMBs]) and their spatial distribution remains unclear. Methods: We conducted a retrospective analysis of 93 patients with lacunar stroke with a standardized investigational magnetic resonance imaging protocol using a 3T scanner. WMH and PVSs were segmented semi-automatically, and lacunes and CMBs were manually segmented. We assessed the univariable associations of four common VRFs (hypertension, hyperlipidemia, diabetes, and smoking) with the load of each cSVD marker. Then, we assessed the independent associations of these VRFs in multivariable regression models adjusted for age and sex. Spatial lesion patterns were explored with regional volumetric comparisons using Pearson’s coefficient analysis, which was adjusted for multiple comparisons, and by visually examining heatmap lesion distributions. Results: Hypertension was the VRF that exhibited stronger associations with the cSVD markers in the univariable analysis. In the multivariable analysis, only lacunes (p = 0.009) and PVSs in the basal ganglia (p = 0.014) and white matter (p = 0.016) were still associated with hypertension. In the regional analysis, hypertension showed a higher WMH load in deep structures and white matter, particularly in the posterior periventricular regions. In patients with hyperlipidemia, WMH was preferentially found in hippocampal regions. Conclusions: Hypertension was confirmed to be the VRF with the most impact on cSVD load, especially for lacunes and PVSs, while the lesion topography was variable for each VRF. These findings shed light on the complexity of cSVD expression in relation to factors detrimental to vascular health. Full article

Background: Type 2 diabetes is linked to impaired cognitive function, but the underlying mechanisms remain poorly understood. As white matter hyperintensities (WMHs) are common in diabetes and associated with vascular brain injury, we investigated whether WMH burden mediates the relationship between hemoglobin A1c (HbA1c) levels and cognition. Methods: We quantified WMH load using the Fazekas scale and conducted a mediation analysis with HbA1c as the independent variable, Fazekas scale as the mediator, and MoCA scores as the outcome variable. Results: WMHs partially mediated the relationship between HbA1c levels and MoCA scores (indirect effect = −0.224, 95% CI = −0.619 to −0.050, p = 0.001), accounting for approximately 15.6% of the total effect. Conclusions: This study suggests that WMHs partially mediate the association between chronically elevated blood glucose levels and cognitive impairment in neurologically healthy adults, supporting a potential microvascular mechanism in diabetes-related cognitive impairment. Full article

Background: Inflammatory arthritides (IAs) are systemic inflammatory syndromes that can affect diverse body tissues. Central nervous system involvement has been reported, but is considered rare. We investigated the relationship between cardiac and subclinical brain involvement in patients with IAs. Methods: We consecutively enrolled 25 patients with IAs and 31 as disease controls with non-autoimmune cardiovascular diseases (CVDs) reporting cardiac symptoms. Each participant underwent combined brain/heart magnetic resonance imaging (MRI). We also recruited 25 consecutive asymptomatic healthy controls without CVDs who underwent brain MRI. MRI scans were performed on a 1.5 T system. We investigated cardiac function/tissue characterization and the presence/localization of white matter hyperintensities (WMHs). Results: All groups had similar ages (p = 0.267), and 16 (64%) patients with IAs vs. 7 (23%) disease controls vs. 16 (64%) healthy controls were women (p = 0.001). WMHs were detected in ≥1 brain area in 15 (60%) patients with IAs and 16 (53%) disease controls (p = 0.620). WMHs were significantly less prevalent amongst healthy controls [two (8%)] compared to patients with IAs (p < 0.001). Amongst patients with IAs, an increased cardiac T2 ratio was associated with an increased probability of WMH occurrence [OR per 0.1 unit change (95% CI): 1.29 (1.05–1.59), p = 0.016], while a higher cardiac T2 ratio (per 0.1 unit change) and extracellular volume fraction (ECV) were associated with higher WMH lesion burdens [β (95% CI): 0.12 (0.03–0.20), p = 0.008 and 0.25 (0.00–0.49), p = 0.049, respectively]. Conclusions: Patients with IAs and cardiac symptoms had significantly higher subclinical WMH burdens compared to age/sex-matched healthy controls. Myocardial edema was associated with a greater WMH burden, potentially suggesting shared pathophysiologic substrates. Full article

Objectives: This study aimed to investigate the relationship between osteoporosis and cerebral small vessel disease (CSVD) burden in stroke-free individuals, as well as its specific imaging markers, including lacunes, enlarged perivascular spaces (EPVSs), white matter hyperintensities (WMHs), and brain atrophy (BA). Methods: A total of 684 stroke-free patients who underwent both bone mineral density (BMD) assessments and brain MRI were included. Clinical data, CSVD burden scores, imaging markers of CSVD, and bone density parameters were collected. Logistic regression models were used to evaluate the relationship between BMD and CSVD burden and imaging markers. Results: Osteoporosis, including hip and vertebral osteoporosis, was independently associated with CSVD burden (OR = 2.332, 95%CI: [1.345, 4.039], p = 0.003; OR = 2.598, 95%CI: [1.540, 4.384], p < 0.001; OR = 1.515, 95%CI: [1.010, 2.272], p = 0.044). Increased BMD in the hip and spine correlated with reduced CSVD burden (OR = 0.929, 95%CI: [0.887, 0.972], p = 0.001; OR = 0.952, 95%CI: [0.917, 0.989], p = 0.012). Hip osteoporosis was a risk factor for lacunes (OR = 2.215, 95%CI: [1.197, 4.1], p = 0.011), multiple lacunes (OR = 2.274, 95%CI: [1.039, 4.980], p = 0.04), severe WMH (OR = 2.611, 95%CI: [1.171, 5.823], p = 0.019), and EPVS ≥ 2 (OR = 1.99, 95%CI: [1.133, 3.495], p = 0.017). No significant association was found between osteoporosis and BA (p = 0.928). In sex-stratified analyses, both hip and vertebral osteoporosis were independently associated with a higher CSVD burden in female patients (hip: OR = 2.529, 95%CI: [1.122, 5.703], p = 0.025; vertebral: OR = 3.129, 95%CI: [1.517, 6.455], p = 0.002; general osteoporosis: OR = 1.755, 95%CI: [1.057, 2.912], p = 0.03), whereas no significant association was observed in male patients (all p > 0.05). Conclusions: Osteoporosis was independently associated with an increased burden of CSVD, particularly evident in female patients. These findings suggest that bone health may be important in CSVD management, particularly for women. Full article

Perivascular spaces (PVS) support metabolic clearance in the brain and are increasingly recognized as key contributors to dementia pathogenesis. Plasma-based biomarkers, such as glial fibrillary acidic protein (GFAP) and the amyloid β42/40 (Aβ42/40) ratio, show promise in dementia diagnosis but remain understudied in vascular cognitive impairment (VCI). VCI, a major global cause of cognitive decline, may be more prevalent in Southeast Asia. Despite its impact, it is underdiagnosed compared to Alzheimer’s, highlighting the need for early, reliable markers. This study aims to examine how these biomarkers relate to PVS burden and domain-specific cognitive outcomes in VCI. VCI was defined as global cognition as assessed by a Montreal Cognitive Assessment Score <26, along with the presence of confluent white matter hyperintensities (deep white matter hyperintensities score >2 or periventricular hyperintensities >3), and >1 lacuna. A total of 108 participants (mean age of 67.3 years, 51.9% female) were included. Multivariate ordinal regression assessed biomarker associations with PVS grade, adjusting for age and diastolic blood pressure. A Aβ42/40 ratio <0.05 and GFAP >54.1 pg/mL were used as biomarker thresholds to subgroup the participants, and the relationship between these thresholds and cognitive performance was analyzed. Elevated GFAP (p = 0.0438) and a reduced Aβ42/40 ratio (p < 0.01) were correlated with a higher PVS grade. In the subgroup with a low Aβ42/40 ratio, a greater PVS burden was associated with poorer executive function (p = 0.045, β = 0.612), while in those with high GFAP levels, it was linked to more pronounced impairments in learning and memory (p = 0.006, β = 0.375). A lower Aβ42/40 ratio and higher GFAP levels track greater PVS burden in VCI. PVS severity may be associated with domain-specific cognitive decline, highlighting the potential utility of these biomarkers in refining clinical assessments and monitoring disease progression. Full article

Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood–brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging. As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood–brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD. Full article

Background/Objectives: Low-grade inflammation in the form of microglial activation may be involved in neurodegenerative and vascular dementias. Subcortical small-vessel disease (SSVD) is the main form of vascular dementia, associated with brain barrier dysfunction and endothelial and monocyte activation. IL-6 and IL-17A are known proinflammatory cytokines that contribute to the disruption of blood–brain barrier integrity and microvascular dysfunction, features that are central to SSVD pathophysiological pathways. We herein compared cerebrospinal fluid (CSF) IL-6 and IL-17A concentrations in SSVD and AD patients as well as control subjects and examined the potential associations among IL-6 and IL-17A levels with cognitive and ΜRΙ changes. The albumin quotient (Qalb) was also calculated. Methods: CSF IL-6 and IL-17A (18 SSVD, 17 AD, and 12 healthy controls) were measured with solid-phase sandwich ELISAs, while albumin levels were measured by immunonephelometry. MMSE, FAB, and the CLOX tests were used for cognitive assessment and MRI was used for atrophy and white matter hyperintensities. Results: Significantly elevated CSF levels of Qalb and IL-6 were found in SSVD patients compared to both AD (p = 0.02) and controls (p = 0.002), respectively. Moreover, CSF IL-6 levels displayed a significant inverse correlation with CLOX2 scores (r = −0.641, p = 0.02), as well as a positive correlation with the total normalized CSF volume (r = 0.7, p = 0.01). CSF IL-17A levels were found to be reduced in SSVD patients, compared to controls and AD patients (p < 0.0001 and p = 0.002, respectively). The IL-6/IL-17A ratio with a cut-off value > 1.004 displayed a sensitivity of 83.33% (95%CI; 60.78% to 94.16%) and a specificity of 68.97% (95%CI; 50.77% to 82.72%) for the discrimination of SSVD from AD patients and controls. Conclusions: In the present pilot single-center study, we found increased CSF IL-6 and IL-6/IL-17A ratio levels in SSVD patients that correlated with reduced scores in the CLOX2 test and increased CSF volume. These preliminary findings deserve further evaluation in larger cohorts in order to elucidate their potential as surrogate biomarkers for the discrimination of SSVD from AD pathology. Full article

Genetic variants increase the risk of neurocognitive disorders in later life, including vascular dementia (VaD) and Alzheimer’s disease (AD), but the precise relationships between genetic risk factors and underlying disease etiologies are not well understood. Transcriptome-wide association studies (TWASs) can be leveraged to better characterize the genes and biological pathways underlying genetic influences on disease. To date, almost all existing TWASs on VaD and AD have been conducted using expression studies from individuals of a single genetic ancestry, primarily European. Using the joint likelihood-based inference framework in Multi-ancEstry TRanscriptOme-wide analysis (METRO), we leveraged gene expression data from European ancestry (EA) and African ancestry (AA) samples to identify genes associated with general cognitive function, white matter hyperintensity (WMH), and AD. Regions were fine-mapped using Fine-mapping Of CaUsal gene Sets (FOCUS). We identified 266, 23, 69, and 2 genes associated with general cognitive function, WMH, AD (using EA GWAS summary statistics), and AD (using AA GWAS), respectively (Bonferroni-corrected alpha = p < 2.9 × 10⁻⁶), some of which had been previously identified. Enrichment analysis showed that many of the identified genes were in pathways related to innate immunity, vascular dysfunction, and neuroinflammation. Further, the downregulation of ICA1L was associated with a higher WMH and with AD, indicating its potential contribution to overlapping AD and VaD neuropathology. To our knowledge, our study is the first TWAS on cognitive function and neurocognitive disorders that used expression mapping studies for multiple ancestries. This work may expand the benefits of TWASs beyond a single ancestry group and help to identify gene targets for pharmaceuticals or preventative treatments for dementia. Full article