Seol-Heui Han

Moon Y, et al. J Clin Neurol. 2026 ;22:e46. https://doi.org/10.3988/jcn.2025.0686

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPS) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPS) associated with AD and new candidates under development for the treatment of NPS based on their therapeutic targets and mechanisms. On top of the conventional NPS studied so far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanisms of action focused on AD-related NPS rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPS in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

Background: The impact of blood–brain barrier (BBB) leakage on white matter hyperintensity (WMH) subtypes (location) and its association with clinical factors and cognition remains unclear.Purpose: To investigate the relationship between WMH volume, permeability, clinical factors, and cognition in older individuals across the cognitive spectrum.Study Type: Prospective, cross‐sectional.Subjects: A total of 193 older adults with/without cognitive impairment; 128 females; mean age 70.1 years (standard deviation 6.8).Field Strength/Sequence: 3 T, GE Dynamic contrast‐enhanced, three‐dimensional (3D) Magnetization‐prepared rapid gradient‐echo (MPRAGE T1WI), 3D fluid‐attenuated inversion recovery (FLAIR).Assessment: Periventricular WMH (PWMH), deep WMH (DWMH), and normal‐appearing white matter (NAWM) were segmented using FMRIB automatic segmentation tool algorithms on 3D FLAIR. Hippocampal volume and cortex volume were segmented on 3D T1WI. BBB permeability (Ktrans) and blood plasma volume (Vp) were determined using the Patlak model. Vascular risk factors and cognition were assessed.Statistical Tests: Univariate and multivariate analyses were performed to identify factors associated with WMH permeability. Logistic regression analysis assessed the association between WMH imaging features and cognition, adjusting for age, sex, apolipoprotein E4 status, education, and brain volumes. A P‐value −3 minute⁻¹) compared to DWMH (0.496 ± 0.478 × 10⁻³ minute⁻¹) and NAWM (0.476 ± 0.398 × 10⁻³ minute⁻¹). Smaller PWMH volume and cardiovascular disease (CVD) history were significantly associated with higher Ktrans in PWMH. In DWMH, higher Ktrans were associated with CVD history and cortical volume. In NAWM, it was linked to CVD history and dyslipidemia. Larger PWMH volume (odds ratio [OR] 1.106, confidence interval [CI]: 1.021–1.197) and smaller hippocampal volume (OR 0.069; CI: 0.019–0.253) were independently linked to worse global cognition after covariate adjustment.Data Conclusion: Elevated BBB leakage in PWMH was associated with lower PWMH volume and prior CVD history. Notably, PWMH volume, rather than permeability, was correlated with cognitive decline, suggesting that BBB leakage in WMH may be a consequence of CVD rather than indicate disease progression.Level of Evidence: 2Technical Efficacy: Stage 3

Neuroinflammation plays a vital role in neurodegenerative diseases and neuropsychiatric disorders, and microglia and astrocytes chiefly modulate inflammatory responses in the central nervous system (CNS). Toll-like receptors (TLRs), which are expressed in neurons, astrocytes, and microglia in the CNS, are critical for innate immune responses; microglial TLRs can regulate the activity of these cells, inducing protective or harmful effects on the surrounding cells, including neurons. Therefore, regulating TLRs in microglia may be a potential therapeutic strategy for neurological disorders. We examined the protective effects of GSP1-111, a novel synthetic peptide for inhibiting TLR signaling, on neuroinflammation and depression-like behavior. GSP1-111 decreased TLR2 expression and remarkably reduced the mRNA expression of inflammatory M1-phenotype markers, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6, while elevating that of the M2 phenotype markers, Arg-1 and IL-10. In vivo, GSP1-111 administration significantly decreased the depression-like behavior induced by lipopolysaccharide (LPS) in a forced swim test and significantly reduced the brain levels of M1-specific inflammatory cytokines (TNFα, IL-1β, and IL-6). GSP1-111 prevented the LPS-induced microglial activation and TLR2 expression in the brain. Accordingly, GSP1-111 prevented inflammatory responses and induced microglial switching of the inflammatory M1 phenotype to the protective M2 phenotype. Thus, GSP1-111 could prevent depression-like behavior by inhibiting TLR2. Taken together, our results suggest that the TLR2 pathway is a promising therapeutic target for depression, and GSP1-111 could be a novel therapeutic candidate for various neurological disorders.

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPSs) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPSs) associated with AD and new candidates under development for the treatment of NPSs based on their therapeutic targets and mechanisms. On top of the conventional NPSs studied far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanism of action focused on AD-related NPS, rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPSs in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

Introduction This multicentre, randomised, open-label, and prospective study aimed to evaluate the effectiveness of memantine (memantine solution) on speech function in patients with moderate to severe Alzheimer’s disease (AD) who were already on donepezil therapy. Methods Participants were divided into two groups: the drug trial group was administered donepezil + memantine (memantine solution), while the control group was administered only donepezil. Patients in the test group were required to increase the dose of memantine by 5 mg/day per week for the first 4 weeks and were maintained at 20 mg/day until the end of the trial. Results Of the 188 participants, 24 dropped out, and 164 completed the final research process. As the primary outcome, K-WAB showed an increase in scores in both groups compared to baseline scores; however, the difference was not statistically significant (P = 0.678). After 12 weeks, the donepezil treatment group had higher K-MMSE and lower CDR-SB scores than the donepezil and memantine combination group, indicating better cognitive and functional status. However, this effect was not sustained for 24 weeks. Patients who were assigned to receive only donepezil had Relevant Outcome Scale for AD (ROSA) scores that were higher by an average of 4.6 points compared to the donepezil and memantine combination group. The NPI-Q index improved compared to baseline values in both groups. Conclusions Although several clinical studies have reported significant improvements in speech function after the administration of memantine, clinical studies on speech function improvement in patients with Alzheimer’s disease are still insignificant. There are no studies on the effect of donepezil and memantine in combination treatment on language function in the moderate and severe stages of AD. Therefore, we investigated the effect of memantine (memantine solution) on speech function in patients with moderate to severe AD who were administered donepezil at a stable dose. Although the efficacy of the combination therapy was not superior to that of donepezil monotherapy alone, memantine was effective in improving behavioural symptoms in patients with moderate or severe AD.

Sleep is a restorative period that plays a crucial role in the physiological functioning of the body, including that of the immune system, memory processing, and cognition. Sleep disturbances can be caused by various physical, mental, and social problems. Recently, there has been growing interest in sleep. Maydis stigma (MS, corn silk) is a female maize flower that is traditionally used as a medicinal plant to treat many diseases, including hypertension, edema, and diabetes. It is also used as a functional food in tea and other supplements. β-Sitosterol (BS) is a phytosterol and a natural micronutrient in higher plants, and it has a similar structure to cholesterol. It is a major component of MS and has anti-inflammatory, antidepressive, and sedative effects. However, the potential effects of MS on sleep regulation remain unclear. Here, we investigated the effects of MS on sleep in mice. The effects of MS on sleep induction were determined using pentobarbital-induced sleep and caffeine-induced sleep disruption mouse models. MS extracts decreased sleep latency and increased sleep duration in both the pentobarbital-induced sleep induction and caffeine-induced sleep disruption models compared to the positive control, valerian root extract. The butanol fraction of MS extracts decreased sleep latency time and increased sleep duration. In addition, β-sitosterol enhances sleep latency and sleep duration. Both MS extract and β-sitosterol increased alpha activity in the EEG analysis. We measured the mRNA expression of melatonin receptors 1 and 2 (MT1/2) using qRT-PCR. The mRNA expression of melatonin receptors 1 and 2 was increased by MS extract and β-sitosterol treatment in rat primary cultured neurons and the brain. In addition, MS extract increased the expression of clock genes including per1/2, cry1/2, and Bmal1 in the brain. MS extract and β-sitosterol increased the phosphorylation of ERK1/2 and αCaMKII. Our results demonstrate for the first time that MS has a sleep-promoting effect via melatonin receptor expression, which may provide new scientific evidence for its use as a potential therapeutic agent for the treatment and prevention of sleep disturbance.

Apolipoprotein (APOE) is implicated and verified as the main risk factor for early-onset Alzheimer's disease (AD). APOE is a protein that binds to lipids and is involved in cholesterol stability. Our paper reports a case of a sporadic early-onset AD (sEOAD) patient of a 54-year-old Korean man, where a novel APOE Leu159Pro heterozygous mutation was revealed upon Whole Exome Sequence analysis. The proband's CSF showed downregulated levels of Aβ42, with unchanged Tau levels. The mutation is in the Low-Density Lipoprotein Receptor (LDLR) region of the APOE gene, which mediates the clearance of APOE lipoproteins. LDLR works as a high-affinity point for APOE. Studies suggest that APOE-LDLR interplay could have varying effects. The LDLR receptor pathway has been previously suggested as a therapeutic target to treat tauopathy. However, the APOE-LDLR interaction has also shown a significant correlation with memory retention. Leu159Pro could be an interesting mutation that could be responsible for a less damaging pattern of AD by suppressing tau-association neurodegeneration while affecting the patient's memory retention and cognitive performance.

Han HJ, et al. J Clin Neurol. 2022 Jul;18(4):428-436. https://doi.org/10.3988/jcn.2022.18.4.428

Cognitive decline is one of the most relevant signs of sarcopenia; however, it is challenging to perform tests for sarcopenia in patients with dementia. In a recent study, temporalis muscle thickness (TMT), an alternative to appendicular muscle mass (ASM), was found to be a valid index for screening sarcopenia. This study aimed to determine whether TMT correlates with ASM and evaluate the relationship between TMT and cognitive function in dementia patients. We recruited patients with a complaint of memory loss who visited the Memory Clinic of Konkuk University Medical Center between November 2014 and December 2020. Patients with probable Alzheimer’s disease (AD) without weakness were included. TMT was measured on axial T1-weighted magnetic resonance (MR) images, perpendicular to the long axis of the temporal muscle, at the orbital roof level. ASM was measured using body dual-energy X-ray absorptiometry (DXA). It was calculated as the sum of lean soft tissue mass in the arms and legs, and the value by ASM divided by height squared was used. Inter-rater reliability and intra-rater reliability were good and excellent, respectively. We found a correlation between TMT and skeletal ASM, which was obtained from cranial MR images and DXA, respectively (r = 0.379, p = 0.001). TMT was negatively correlated with age (r = − 0.296, p = 0.014) and positively correlated with body mass index (BMI) (r = 0.303, p = 0.012). Additionally, TMT was correlated with MMSE (r = 0.350, p = 0.003). After adjusting for educational years, there was still a correlation between TMT and MMSE (r = 0.256, p = 0.038). This study demonstrated that TMT correlates with ASM and cognitive function in patients with dementia. Measuring TMT using cranial MR images could help diagnose sarcopenia accessibly and assess cognitive function in patients with dementia.