Yeong-Bae Lee

Objectives: Early non-pharmacological interventions for people with subjective memory decline (SMD) are increasingly advocated in preventing age-related cognitive decline and potentially delaying progression to mild cognitive impairment or dementia. In this multicenter clinical trial (RAYDELP1), we evaluated the efficacy and safety of sugarcane-derived Cuban policosanol (PCO) on cognitive function, superoxide dismutase (SOD) activity, inflammatory markers, and metabolic panels in adults aged 55–85 years with subjective cognitive complaints. Methods: A 12-week, randomized, double-blinded, placebo-controlled trial was conducted at Gachon University Gil Medical Center and Seoul Veterans Hospital in adults with SMD complaints. Individuals were randomized equally into three groups: placebo, PCO 20 mg group, or PCO 40 mg group. Assessment of cognitive function was performed using the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog 11) and the Korean Mini-Mental State Examination (K-MMSE). All measurements, including SOD activity, inflammatory markers, and metabolic parameters, were analyzed in blood samples at baseline and after 12 weeks. For an exploratory subgroup analysis, participants receiving statins and those with potential ceiling effects or greater cognitive impairment based on K-MMSE scores were excluded. The K-MMSE range of 18–26 was used as an exploratory criterion to reduce heterogeneity in baseline cognitive scores, resulting in a refined analysis population of 56 participants. Results: In the refined SMD population, SOD activity increased significantly in the PCO 40 mg group after 12 weeks (mean change, +0.16 ± 0.25 U/mL; p = 0.0109) with increasing HDL-C, whereas changes in the placebo groups were not statistically significant (+0.08 ± 0.24 U/mL, p = 0.1873) with decreasing HDL-C. HDL-C levels increased in a dose-dependent manner in both the PCO 20 mg (+0.78 ± 5.1 mg/dL) and PCO 40 mg (+2.2 ± 6.7 mg/dL) groups within and between the groups. Both PCO groups showed significant differences compared with placebo in the between-group analysis and baseline-adjusted ANCOVA (p = 0.0124 and p = 0.0142, respectively). K-MMSE place-orientation scores improved significantly from baseline within both PCO groups (20 mg: 0.94 ± 0.87, p = 0.0003; 40 mg: 0.47 ± 0.77, p = 0.0155), whereas no significant within-group change was observed in the placebo group. Similarly, ADAS-Cog 11 language scores improved significantly within both PCO groups (20 mg: −1.17 ± 1.92, p = 0.0194; 40 mg: −0.95 ± 1.58, p = 0.0176). The 20 mg PCO group also showed a significant within-group decrease in Visual CPT false-alarm errors (−3.83 ± 7.13, p = 0.0357). However, between-group comparisons and baseline-adjusted ANCOVA did not demonstrate statistically significant differences in the selected cognitive outcomes. Conclusions: In the analyzed study population, HDL-C levels increased numerically in both PCO groups in a dose-dependent manner. The PCO 40 mg group showed a significant within-group increase in serum SOD activity, while improvements in selected cognitive domains were observed within both 20 mg and 40 mg PCO groups. However, no significant differences were found in between-group or ANCOVA analyses. PCO was well tolerated, and further clinical studies are warranted to confirm these exploratory findings and clarify its potential effects on cognitive function and enhancement of HDL quantity and quality.

Mitofusin-2 (MFN2) variants are a well-established cause of Charcot–Marie–Tooth disease type 2A, although central nervous system involvement has increasingly been recognized in a subset of affected patients. We report a 51-year-old woman carrying a likely pathogenic MFN2 variant (c.2119C>T, p.Arg707Trp) who developed rapidly progressive spastic paraplegia and became wheelchair-dependent within several months. Neurological examination demonstrated severe pyramidal tract signs with preserved sensory function. Nerve conduction studies were suggestive of distal motor axonal involvement, while transcranial magnetic stimulation and somatosensory evoked potentials indicated corticospinal and central sensory pathway dysfunction in the lower extremities. Brain magnetic resonance imaging revealed extensive bilateral confluent periventricular and deep white matter hyperintensities. Comprehensive investigations excluded inflammatory, vascular, metabolic, infectious, neoplastic, and common genetic causes of hereditary spastic paraplegia. Targeted next-generation sequencing identified a heterozygous likely pathogenic MFN2 p.Arg707Trp variant. Although central nervous system manifestations have previously been described in MFN2-related disease, this phenotype is unusual because of the combination of late-onset rapidly progressive spastic paraplegia, and extensive cerebral white matter abnormalities associated with the p.Arg707Trp variant. This case further expands the recognized phenotypic spectrum of MFN2-related disease and highlights that MFN2 variants should be considered in the differential diagnosis of selected patients with late-onset progressive spastic paraplegia accompanied by cerebral white matter abnormalities and distal motor axonal neuropathy.

Background: Current stroke guidelines lack subtype‐specific recommendations for optimal low‐density lipoprotein cholesterol targets. Indeed, most lipid‐lowering trials have not differentiated between stroke subtypes or focused primarily on large artery atherosclerosis, leaving a gap in evidence for other stroke subtypes, such as small vessel occlusion stroke. This study is designed to evaluate whether intensive lipid‐lowering therapy is superior to standard therapy in reducing major adverse cardiovascular events among patients with small vessel occlusion stroke. Methods: SVO70 (Optimal Target Low‐Density Lipoprotein Cholesterol Level for Small Vessel Occlusion Stroke) is a multicenter, prospective, randomized, open, blinded‐end point clinical trial in which adult patients with neuroimaging‐confirmed small vessel occlusion stroke within 180 days of randomization will be enrolled. Key exclusion criteria include predefined low‐density lipoprotein cholesterol targets for other comorbidities, contraindications to statin, and pregnancy or lactation. Eligible participants will be randomized 1:1 to achieve low‐density lipoprotein cholesterol <70 mg/dL (intensive group) or 90 to 110 mg/dL (standard group). The trial aims to enroll 4016 participants over a 2‐year recruitment period, with a minimum follow‐up of 4 years. The primary end point is the occurrence of major adverse cardiovascular events, defined as cardiovascular death, stroke, and acute coronary syndrome, during the follow‐up period. Secondary end points include (1) any stroke, (2) ischemic stroke or transient ischemic attack, (3) hemorrhagic stroke, (4) cardiovascular death, (5) myocardial infarction, (6) all‐cause death, and (7) acute coronary syndrome. Conclusions: This study will provide valuable information for determining optimal low‐density lipoprotein cholesterol targets for patients with small vessel occlusion stroke. Registration: URL: https://ClinicalTrials.gov ; Unique Identifier: NCT06649240, Clinical Research Information Service (KCT0009043).

Background and Objectives: Blood flow is critical for tissue oxygenation, and alterations in cerebrovascular and peripheral circulation have important health implications. This study aimed to examine the impact of distinct mechanisms for increasing intra-cavity pressure through the abdominal bracing (AB) and Valsalva maneuver (VM) on central and peripheral hemodynamics. Materials and Methods: A randomized crossover design was used, and thirty healthy young adults (age 21.9 ± 1.5 years; BMI 20.9 ± 1.8 kg/m²) performed AB and VM in a randomized order. All participants provided written informed consent, and the study protocol was approved by the Clinical Research Information Service (KCT0009742; registered on 30 August 2024). Hemodynamic responses were measured before and after each intervention, including heart rate, blood pressure, pulse wave velocity, carotid artery diameter, pulsatility index, resistive index, peripheral oxygen saturation, and cerebral oxygenation. Repeated-measures analysis of variance and paired t-tests were conducted on the datasets. Results: Both the VM and AB significantly increased heart rate (p < 0.001) and systolic blood pressure (VM: p = 0.015; AB: p < 0.001). Cerebral oxygen saturation decreased significantly (VM: p < 0.05; AB: p < 0.05), whereas oxyhemoglobin increased during both interventions, suggesting higher cerebral oxygen demand. The VM specifically increased the carotid pulsatility index (pre = 1.76 ± 0.28; post2 = 1.87 ± 0.33; p = 0.008), reflecting elevated central vascular resistance. In contrast, AB decreased peripheral oxygen saturation (pre = 98.43 ± 0.71; post1 = 97.49 ± 1.76; p < 0.001) and increased peripheral (heart–finger) pulse wave velocity (Lt: p = 0.026; Rt: p = 0.010), indicating greater stimulation of peripheral circulation. Conclusions: Distinct mechanisms that elevate intra-cavity pressure differentially influence central and peripheral hemodynamics. These findings suggest that intra-cavity pressure can selectively modulate hemodynamic responses, with potential applications in both clinical and exercise settings.

Assessment of cerebrovascular function is crucial for managing neurological disorders, with cerebral blood flow (CBF) measurement being key. Single photon emission computed tomography (SPECT), a traditional method, uses radiation exposure. Blood oxygenation level-dependent (BOLD) magnetic resonance imaging (MRI) with carbon dioxide (CO₂) is a non-invasive cerebrovascular reactivity (CVR) alternative, but direct SPECT-MRI CO₂ comparisons for MRI’s replacement potential are limited. This study directly compared CVR from SPECT and MRI CO₂ in nine healthy participants. Delay-based MRI (tcMRI) with stimulus timing correction was analyzed alongside conventional MRI. Results showed no significant CVR differences between SPECT and tcMRI (p = 0.688) or SPECT and conventional MRI (p = 0.813), indicating comparable overall CVR. However, tcMRI significantly differed from conventional MRI (p = 0.016) and showed a greater similarity to SPECT. Regionally, the largest CVR differences were observed between tcMRI and conventional MRI, particularly in the cingulate cortex, frontal lobe, and basal ganglia. These discrepancies suggest that tcMRI may capture subtle CVR abnormalities not detected by conventional MRI. The findings support the clinical utility of CO₂-MRI, especially with stimulus timing correction, as a safe, repeatable, and radiation-free alternative to SPECT. In particular, tcMRI may offer advantages for repeated CVR assessments in long-term clinical monitoring.

Early neurological deterioration (END) occurs in individuals who had experienced acute ischemic stroke (AIS), impacting long-term functional outcomes. We aimed to investigate the association between endothelial function, measured via flow-mediated dilation (FMD), and END in patients with AIS. We retrospectively reviewed patients who had experienced AIS within 7 days of stroke onset and underwent FMD assessments during their hospitalization (%FMD = Peak diameter − baseline diameter)/baseline diameter x 100). END was defined as ≥ 2-point increase in the National Institutes of Health Stroke Scale total score or ≥ 1-point increase in the motor score within 72 h post-stroke. Through multivariate analysis, we examined factors associated with END and explored the relationship between FMD and END with considering stroke mechanisms. Among 1,262 patients diagnosed with AIS, 184 (14.6%) experienced END. Those with END were on average older (69 ± 13 vs. 67 ± 13 years; P = 0.033), had a higher prevalence of stroke history (21.2 vs. 12.9%; P = 0.003), and lower FMD (5.0 ± 1.8 vs. 5.4 ± 2.2%; P = 0.029). Multivariate analysis revealed that a history of stroke (adjusted odds ratio [aOR] = 1.728; 95% confidence interval [CI] 1.159–2.578; P = 0.007) and low % were independently associated with END. Subgroup analysis revealed that low %FMD was significantly associated with END within the small vessel disease (SVD) category (aOR = 0.789; 95% CI 0.679–0.920; P = 0.002). Impaired FMD may be associated with END, particularly within the context of SVD.

Compared with other organs in the body, the human brain is extremely sensitive to changes in O₂ and CO₂ levels. This study applied functional near-infrared spectroscopy (fNIRS) to analyze the changes in cerebral oxygen saturation (COS) and hemoglobin (Hb) concentrations in response to various atmospheric gas concentrations and investigate their effects on brain function. Twenty-nine adults were exposed to four gas conditions, namely atmospheric concentration (C1), high O₂ concentration (C2), high CO₂ concentration (C3), and high O₂ and CO₂ concentrations (C4). Changes in COS and Hb concentrations were measured using fNIRS, whereas heart rate (HR) and percutaneous oxygen saturation (SpO₂) were measured using a patient monitor. COS, oxy-Hb (HbO), and total-Hb (HbT) increased progressively from C1 to C4, whereas deoxy-Hb (HbR) exhibited a decreasing trend. Moreover, the COS and Hb concentrations were more strongly influenced by high CO₂ levels than by high O₂ levels. High O₂ concentrations increased the blood O₂ saturation, whereas high CO₂ concentrations increased blood flow as a physiological response, enhancing O₂ delivery to the brain. Additionally, HR and SpO₂ increased at high CO₂ concentrations. However, at high O₂ concentrations providing a sufficient O₂ supply, SpO₂ increased while HR decreased. Therefore, adjusting the concentrations of CO₂ and O₂ may improve cerebral blood flow and change brain function, supporting cerebrovascular health and preventing related diseases.

This study aimed to investigate the effects of Valsalva maneuver (VM) with the controlled expiratory pressures on vascular stiffness of common carotid artery (CCA) and cerebral hemodynamic changes using diagnostic ultrasonography. Twenty-seven healthy participants (mean and standard deviation of age = 22.78 ± 1.89) performed 30 and 40 mmHg VM. The right CCA stiffness index and pulse wave velocity (PWV) were measured before (PRE) and after (POST) VM. The peak systolic velocity (PSV), resistance index (RI), and heart rate (HR) were measured before (PRE) and after (POST1 and POST2 during the first and the second 15 s, respectively) VM. Near-infrared spectroscopy (NIRS) was utilized to measure regional oxygen saturation (rSO2) and oxyhemoglobin (HbO) on the left and right prefrontal cortex. Stiffness index decreased by 1.76 (p < 0.001) from PRE to POST only after 30 mmHg VM. PWV decreased by 0.69 m/s (p < 0.001, 30 mmHg) and 0.34 m/s (p = 0.022, 40 mmHg) in POST. Conversely, PSV increased by 5.36 cm/s (p = 0.031, 30 mmHg) and 4.77 cm/s (p = 0.04, 40 mmHg) in POST2. Increase in RI (p = 0.017) and decrease in HR (p = 0.003) occurred only after the 40 mmHg VM. Right HbO decreased after 30 mmHg VM (p = 0.023) from PRE to POST1, and right rSO2 increased after 40 mmHg VM (p = 0.036) from VM (during) to POST1. Both 30 and 40 mmHg VM showed a significant improvement in PWV and an increase in PSV. However, at 30 mmHg VM, a significant decrease in HbO was observed after VM owing to increased cerebral oxygen exchange, and at 40 mmHg VM, an rSO2 increase was observed after VM owing to high vascular pressure. Additionally, the increased pressure and rSO2 at 40 mmHg may have been caused by increased RI. The results indicated that the 30 mmHg VM was more effective on CCA stiffness than the 40 mmHg VM.