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Blood-based biomarkers (BBM) are potentially powerful tools that assist in the biological diagnosis of Alzheimer's disease (AD) in vivo with minimal invasiveness, relatively low cost, and good accessibility. This review summarizes current evidence for using BBMs in AD, focusing on amyloid, tau, and biomarkers for neurodegeneration. Blood-based phosphorylated tau and the Aβ42/Aβ40 ratio showed consistent concordance with brain pathology measured by CSF or PET in the research setting. In addition, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are neurodegenerative biomarkers that show the potential to assist in the differential diagnosis of AD. Other pathology-specific biomarkers, such as α-synuclein and TAR DNA-binding protein 43 (TDP-43), can potentially detect AD concurrent pathology. Based on current evidence, the working group from the Taiwan Dementia Society (TDS) achieved consensus recommendations on the appropriate use of BBMs for AD in clinical practice. BBMs may assist clinical diagnosis and prognosis in AD subjects with cognitive symptoms; however, the results should be interpreted by dementia specialists and combining biochemical, neuropsychological, and neuroimaging information. Further studies are needed to evaluate BBMs' real-world performance and potential impact on clinical decision-making.

Abstract Background There have been limited data on idiopathic intracranial hypertension (IIH) in Asians and there remain uncertainties whether a cerebrospinal fluid (CSF) pressure of 250 mm CSF is an optimum diagnostic cutoff. The aims of the present study included (1) characterization of IIH patients in Taiwan, (2) comparisons among different diagnostic criteria for IIH, and (3) comparisons between patients with CSF pressures of > 250 and 200–250 mm CSF. Methods This retrospective study involved IIH patients based on the modified Dandy criteria from two tertiary medical centers in Taiwan. Clinical manifestations were retrieved from electronic medical records, and findings on ophthalmologic examination and magnetic resonance images (MRIs) were reviewed. Results A total of 102 patients (71 F/31 M, mean age 33.4 ± 12.2 years, mean CSF pressure 282.5 ± 74.5 mm CSF) were identified, including 46 (45.1%) with obesity (body-mass index ≥ 27.5), and 57 (62.6%) with papilledema. Overall, 80 (78.4%), 55 (53.9%), 51 (50.0%), and 58 (56.9%) patients met the Second and Third Edition of International Classification of Headache Disorders, Friedman, and Korsbæk criteria, respectively. Patients in the 200–250 mm CSF group (n = 40) were less likely to have papilledema (48.5% vs. 70.7%, p = 0.035), transient visual obscuration (12.5% vs. 33.9%, p = 0.005), and horizontal diplopia (10.0% vs. 30.6%, p = 0.006), and had fewer signs on MRIs (2.2 ± 1.3 vs. 2.8 ± 1.0, p = 0.021) when compared with those with CSF pressures > 250 mm CSF (n = 62). However, the percentages of patients with headache (95.0% vs. 87.1%, p = 0.109) at baseline, chronic migraine at six months (31.6% vs. 25.0%, p = 0.578), and visual field defect (86.7% vs. 90.3%, p = 0.709) were similar. Conclusions It was found that obesity and papilledema were less common in Asian IIH patients when compared with Caucasian patients. Although patients with CSF pressures of 200–250 mm CSF had a less severe phenotype, the risks of having headache or visual loss were comparable to those in the > 250 mm CSF group. It is possible that a diagnostic cutoff of > 200 mm CSF could be more suitable for Asians, although further studies are still needed.

Background: Health-related quality of life (HRQoL) is an essential outcome parameter in geriatric research; however, the available evidence is mixed regarding the factors associated with HRQoL among people with dementia. We aimed to identify factors that contribute to HRQoL among people with dementia in residential long-term care (LTC) institutions. Methods: We randomly selected 299 of 1607 registered residential LTC institutions in Taiwan. A cross-sectional survey was conducted between 2019 and 2020, including items on demographic characteristics, comorbidities, the EuroQol-5 dimensions-5 levels (EQ-5D-5L; utility and visual analog scale [VAS] scores), the Mini-Mental State Examination (MMSE), the Clinical Dementia Rating (CDR), behavioral and psychological symptoms of dementia, activities of daily living (ADL), and instrumental ADL (IADL). Results: In total, 1313 people with dementia from 267 institutions were enrolled (mean age, 76.4 ± 12.7 years). The mean EQ-5D-5L utility and VAS scores were 0.10 (standard deviation [SD] = 0.48) and 66.57 (SD = 20.67), respectively. In multivariate linear regression analysis, higher scores for ADL, IADL, and CDR sum of boxes were associated with higher utility scores. Higher VAS scores were associated with higher ADL and MMSE scores. Lower utility scores and VAS scores were associated with more frequent depressive symptoms. Conclusion: ADL, dementia severity, cognitive function, and depressive symptoms influenced the HRQoL of people with dementia in residential LTC institutions. Longitudinal studies should be conducted to better understand how HRQoL changes over time among people with disabilities.

Abstract Background The pathophysiology of the reversible cerebral vasoconstriction syndrome (RCVS) remains enigmatic and the role of glymphatics in RCVS pathophysiology has not been evaluated. We aimed to investigate RCVS glymphatic dynamics and its clinical correlates. Methods We prospectively evaluated the glymphatic function in RCVS patients, with RCVS subjects and healthy controls (HCs) recruited between August 2020 and November 2023, by calculating diffusion-tensor imaging along the perivascular space (DTI-ALPS) index under a 3-T MRI. Clinical and vascular (transcranial color-coded duplex sonography) investigations were conducted in RCVS subjects. RCVS participants were separated into acute (≤ 30 days) and remission (≥ 90 days) groups by disease onset to MRI interval. The time-trend, acute stage and longitudinal analyses of the DTI-ALPS index were conducted. Correlations between DTI-ALPS index and vascular and clinical parameters were performed. Bonferroni correction was applied to vascular investigations (q = 0.05/11). Results A total of 138 RCVS patients (mean age, 46.8 years ± 11.8; 128 women) and 42 HCs (mean age, 46.0 years ± 4.5; 35 women) were evaluated. Acute RCVS demonstrated lower DTI-ALPS index than HCs (p

Abstract Background Half of the sufferers of reversible cerebral vasoconstriction syndrome (RCVS) exhibit imaging-proven blood-brain barrier disruption. The pathogenesis of blood-brain barrier disruption in RCVS remains unclear and mechanism-specific intervention is lacking. We speculated that cerebrovascular dysregulation might be associated with blood-brain barrier disruption in RCVS. Hence, we aimed to evaluate whether the dynamic cerebral autoregulation is altered in patients with RCVS and could be associated with blood-brain barrier disruption. Methods A cross-sectional study was conducted from 2019 to 2021 at headache clinics of a national tertiary medical center. Dynamic cerebral autoregulation was evaluated in all participants. The capacity of the dynamic cerebral autoregulation to damp the systemic hemodynamic changes, i.e., phase shift and gain between the cerebral blood flow and blood pressure waveforms in the very-low- and low-frequency bands were calculated by transfer function analysis. The mean flow correlation index was also calculated. Patients with RCVS received 3-dimensional isotropic contrast-enhanced T2 fluid-attenuated inversion recovery imaging to visualize blood-brain barrier disruption. Results Forty-five patients with RCVS (41.9 ± 9.8 years old, 29 females) and 45 matched healthy controls (41.4 ± 12.5 years old, 29 females) completed the study. Nineteen of the patients had blood-brain barrier disruption. Compared to healthy controls, patients with RCVS had poorer dynamic cerebral autoregulation, indicated by higher gain in very-low-frequency band (left: 1.6 ± 0.7, p = 0.001; right: 1.5 ± 0.7, p = 0.003; healthy controls: 1.1 ± 0.4) and higher mean flow correlation index (left: 0.39 ± 0.20, p = 0.040; right: 0.40 ± 0.18, p = 0.017; healthy controls: 0.31 ± 0.17). Moreover, patients with RCVS with blood-brain barrier disruption had worse dynamic cerebral autoregulation, as compared to those without blood-brain barrier disruption, by having less phase shift in very-low- and low-frequency bands, and higher mean flow correlation index. Conclusions Dysfunctional dynamic cerebral autoregulation was observed in patients with RCVS, particularly in those with blood-brain barrier disruption. These findings suggest that impaired cerebral autoregulation plays a pivotal role in RCVS pathophysiology and may be relevant to complications associated with blood-brain barrier disruption by impaired capacity of maintaining stable cerebral blood flow under fluctuating blood pressure. Graphical Abstract

Abstract Background Cluster headache is a highly debilitating neurological disorder with considerable inter-ethnic differences. Genome-wide association studies (GWAS) recently identified replicable genomic loci for cluster headache in Europeans, but the genetic underpinnings for cluster headache in Asians remain unclear. The objective of this study is to investigate the genetic architecture and susceptibility loci of cluster headache in Han Chinese resided in Taiwan. Methods We conducted a two-stage genome-wide association study in a Taiwanese cohort enrolled from 2007 through 2022 to identify the genetic variants associated with cluster headache. Diagnosis of cluster headache was retrospectively ascertained with the criteria of International Classification of Headache Disorders, third edition. Control subjects were enrolled from the Taiwan Biobank. Genotyping was conducted with the Axiom Genome-Wide Array TWB chip, followed by whole genome imputation. A polygenic risk score was developed to differentiate patients from controls. Downstream analyses including gene-set and tissue enrichment, linkage disequilibrium score regression, and pathway analyses were performed. Results We enrolled 734 patients with cluster headache and 9,846 population-based controls. We identified three replicable loci, with the lead SNPs being rs1556780 in CAPN2 (odds ratio = 1.59, 95% CI 1.42‒1.78, p = 7.61 × 10–16), rs10188640 in MERTK (odds ratio = 1.52, 95% CI 1.33‒1.73, p = 8.58 × 10–13), and rs13028839 in STAB2 (odds ratio = 0.63, 95% CI 0.52‒0.78, p = 2.81 × 10–8), with the latter two replicating the findings in European populations. Several previously reported genes also showed significant associations with cluster headache in our samples. Polygenic risk score differentiated patients from controls with an area under the receiver operating characteristic curve of 0.77. Downstream analyses implicated circadian regulation and immunological processes in the pathogenesis of cluster headache. Conclusions This study revealed the genetic architecture and novel susceptible loci of cluster headache in Han Chinese residing in Taiwan. Our findings support the common genetic contributions of cluster headache across ethnicities and provide novel mechanistic insights into the pathogenesis of cluster headache.

AimsOur aim was to differentiate patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) from cognitively normal (CN) individuals and predict the progression from MCI to AD within a 3-year longitudinal follow-up. A newly developed Holo-Hilbert Spectral Analysis (HHSA) was applied to resting state EEG (rsEEG), and features were extracted and subjected to machine learning algorithms.MethodsA total of 205 participants were recruited from three hospitals, with CN (n = 51, MMSE > 26), MCI (n = 42, CDR = 0.5, MMSE ≥ 25), AD1 (n = 61, CDR = 1, MMSE < 25), AD2 (n = 35, CDR = 2, MMSE < 16), and AD3 (n = 16, CDR = 3, MMSE < 16). rsEEG was also acquired from all subjects. Seventy-two MCI patients (CDR = 0.5) were longitudinally followed up with two rsEEG recordings within 3 years and further subdivided into an MCI-stable group (MCI-S, n = 36) and an MCI-converted group (MCI-C, n = 36). The HHSA was then applied to the rsEEG data, and features were extracted and subjected to machine-learning algorithms.Results(a) At the group level analysis, the HHSA contrast of MCI and different stages of AD showed augmented amplitude modulation (AM) power of lower-frequency oscillations (LFO; delta and theta bands) with attenuated AM power of higher-frequency oscillations (HFO; beta and gamma bands) compared with cognitively normal elderly controls. The alpha frequency oscillation showed augmented AM power across MCI to AD1 with a reverse trend at AD2. (b) At the individual level of cross-sectional analysis, implementation of machine learning algorithms discriminated between groups with good sensitivity (Sen) and specificity (Spec) as follows: CN elderly vs. MCI: 0.82 (Sen)/0.80 (Spec), CN vs. AD1: 0.94 (Sen)/0.80 (Spec), CN vs. AD2: 0.93 (Sen)/0.90 (Spec), and CN vs. AD3: 0.75 (Sen)/1.00 (Spec). (c) In the longitudinal MCI follow-up, the initial contrasted HHSA between MCI-S and MCI-C groups showed significantly attenuated AM power of alpha and beta band oscillations. (d) At the individual level analysis of longitudinal MCI groups, deploying machine learning algorithms with the best seven features resulted in a sensitivity of 0.9 by the support vector machine (SVM) classifier, with a specificity of 0.8 yielded by the decision tree classifier.ConclusionIntegrating HHSA into EEG signals and machine learning algorithms can differentiate between CN and MCI as well as also predict AD progression at the MCI stage.

Background/Purpose: The long-term disease course and efficacy of maintenance therapies have rarely been investigated in Asian patients with neuromyelitis optica spectrum disorder (NMOSD). Methods: Medical records of patients fulfilling the 2015 International Consensus Diagnostic Criteria for NMOSD at three medical centers in Taiwan were systematically analyzed. Linear regression analysis was performed to investigate factors related to annualized relapse rate (ARR); survival analysis was used to estimate the relapse-free intervals among therapies. Results: A total of 557 relapses affecting 648 regions (202 optic neuritis, 352 acute myelitis, and 94 brain syndromes) in 204 patients were analyzed during a follow-up period of 69.5 months (range, 1–420). Up to 36.1% of myelitis-onset patients and 24.0% of optic neuritis-onset patients exhibited a limited form disease, defined as having one or more relapses confined to the same region. The median ARR was significantly lower in patients with limited form disease than those with relapses involving multiple regions (0.30 vs. 0.47, respectively). An older age at disease onset was associated with a lower ARR (p = 0.023). Kaplan–Meier analysis showed that the estimated time (months) to next relapse was longest in rituximab-treatment group (58.0 ± 13.2), followed by immunosuppressant (48.5 ± 4.8) or prednisone (29.6 ± 4.6) groups, and shortest in those without maintenance therapy (27.6 ± 4.2) (p = 8.1 × 10−7). Conclusion: Limited form disease and older age at disease onset are associated with a lower relapse rate in NMOSD. Compared to no maintenance therapy, rituximab and immunosuppressant significantly reduce the relapse risks.

Background: Neuropsychiatric symptoms (NPS) could increase mortality risk in people with dementia due to Alzheimer's disease (AD). However, whether NPS affects mortality risk in people with mild cognitive impairment (MCI) and whether any specific syndrome of NPS influences this risk are still unclear. Methods: In total, 984 participants with dementia due to AD, 338 with MCI, and 365 controls were enrolled. Over a mean of 5-year follow-up, cause of death data were obtained from the Ministry of Health and Welfare in Taiwan. NPS were assessed using Neuropsychiatric Inventory Questionnaire (NPI-Q), and psychosis, mood, and frontal domain scores were determined. Survival analyses were conducted to determine the hazard ratio (HR) of death. Results: In controlled analyses, HR of death for AD was 2.19 (95% confidence interval [CI] = 1.29–3.71) compared with the control group, whereas no statistical significance was noted for the MCI group. A high NPI-Q score (above the median score) increased mortality risk for both the MCI and AD groups, with HRs of 2.32 (95% CI = 1.07–5.03) and 2.60 (95% CI = 1.51–4.47), respectively. Among NPI-Q domain scores, only high mood domain, but not psychosis or frontal domain, scores increased death risk for both the MCI (HR = 2.89, 95% CI = 1.00–8.51) and AD (HR = 2.59, 95% CI = 1.47–4.55) groups. Conclusion: Mortality risk is high for patients with AD. Not only for AD, patients with MCI presenting with NPS, particularly mood symptoms, have high death risk.

Abstract Background Restless legs syndrome is a highly prevalent comorbidity of migraine; however, its genetic contributions remain unclear. Objectives To identify the genetic variants of restless legs syndrome in migraineurs and to investigate their potential pathogenic roles. Methods We conducted a two-stage genome-wide association study (GWAS) to identify susceptible genes for restless legs syndrome in 1,647 patients with migraine, including 264 with and 1,383 without restless legs syndrome, and also validated the association of lead variants in normal controls unaffected with restless legs syndrome (n = 1,053). We used morpholino translational knockdown (morphants), CRISPR/dCas9 transcriptional knockdown, transient CRISPR/Cas9 knockout (crispants) and gene rescue in one-cell stage embryos of zebrafish to study the function of the identified genes. Results We identified two novel susceptibility loci rs6021854 (in VSTM2L) and rs79823654 (in CCDC141) to be associated with restless legs syndrome in migraineurs, which remained significant when compared to normal controls. Two different morpholinos targeting vstm2l and ccdc141 in zebrafish demonstrated behavioural and cytochemical phenotypes relevant to restless legs syndrome, including hyperkinetic movements of pectoral fins and decreased number in dopaminergic amacrine cells. These phenotypes could be partially reversed with gene rescue, suggesting the specificity of translational knockdown. Transcriptional CRISPR/dCas9 knockdown and transient CRISPR/Cas9 knockout of vstm2l and ccdc141 replicated the findings observed in translationally knocked-down morphants. Conclusions Our GWAS and functional analysis suggest VSTM2L and CCDC141 are highly relevant to the pathogenesis of restless legs syndrome in migraineurs.

Background/purpose: Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited neurodegenerative disorders characterized by slowly progressive lower limbs spasticity and weakness. HSP type 15 (SPG15) is an autosomal recessive subtype caused by ZFYVE26 mutations. The aim of this study was to investigate the frequency and clinical and genetic features of ZFYVE26 mutations in a Taiwanese HSP cohort. Methods: Mutational analysis of the coding regions of ZFYVE26 was performed by targeted resequencing in the 195 unrelated Taiwanese patients with HSP. All of the patients were of Han Chinese ethnicity. Clinical, neuropsychological, electrophysiological evaluations and imaging studies were collected. Results: Among the 195 patients, only one SPG15 patient was identified. The patient had a novel recessive ZFYVE26 frameshift truncating mutation, p.R1806Gfs∗36 (c.5415delC), and presented with insidious onset spastic weakness of lower-extremities and cognitive impairment. Neuropsychological assessment revealed deficits in executive function, visual naming, category verbal fluency, and manual dexterity. Brain MRI showed thin corpus callosum and the “ears of lynx” sign. Conclusion: SPG15 accounts for approximately 0.5% (1/195) of the Taiwanese HSP cohort. This study identified the first Taiwanese SPG15 case and delineated the clinical, genetic, neuropsychological, and neuroimaging features. These findings expand the mutational spectrum of ZFYVE26 and also broaden the knowledge of clinical and neuropsychological characteristics of SPG15.

Abstract Objective Mutations in the colony‐stimulating factor 1 receptor gene (CSF1R) were identified as a cause of adult‐onset inherited leukoencephalopathy. The present study aims at investigating the frequency, clinical characteristics, and functional effects of CSF1R mutations in Taiwanese patients with adult‐onset leukoencephalopathy. Methods Mutational analysis of CSF1R was performed in 149 unrelated individuals with leukoencephalopathy by a targeted resequencing panel covering the entire coding regions of CSF1R. In vitro analysis of the CSF1‐induced autophosphorylation activities of mutant CSF1R proteins was conducted to assess the pathogenicity of the CSF1R mutations. Results Among the eight CSF1R variants identified in this study, five mutations led to a loss of CSF1‐induced autophosphorylation of CSF1R proteins. Four mutations (p.K586*, p.G589R, p.R777Q, and p.R782C) located within the tyrosine kinase domain of CSF1R, whereas the p.T79M mutation resided in the immunoglobulin‐like domain. The five patients carrying the CSF1R mutations developed cognitive decline at age 41, 43, 50, 79, and 86 years, respectively. Psychiatric symptoms and behavior changes were observed in four of the five patients. The executive function and processing speed were severely impaired at an early stage, and their cognitive function deteriorated rapidly within 3–4 years. Diffusion‐restricted lesions at the subcortical regions and bilateral corticospinal tracts were found in three patients. Interpretation CSF1R mutations account for 3.5% (5/149) of the adult‐onset leukoencephalopathy in Taiwan. CSF1R mutations outside the tyrosine kinase domain may also disturb the CSF1R function and lead to the clinical phenotype. Molecular functional validation is important to determine the pathogenicity of novel CSF1R variants.

Introduction: Two common variants of sortilin-related receptor 1 gene (SORL1), rs2298813 and rs1784933, have been associated with late-onset Alzheimer’s disease (AD) in the Han Chinese population in Taiwan. However, neuroimaging correlates of these two SORL1 variants remain unknown. We aimed to determine whether the two SORL1 polymorphisms were associated with any volumetric differences in brain regions in late-onset AD patients.Methods: We recruited 200 patients with late-onset AD from Taipei Veterans General Hospital. All patients received a structural magnetic resonance (MR) imaging brain scan and completed a battery of neurocognitive tests at enrollment. We followed up to assess changes in Mini-Mental State Examination (MMSE) scores in 155 patients (77.5%) at an interval of 2 years. Volumetric measures and cortical thickness of various brain regions were performed using FreeSurfer. Regression analysis controlled for apolipoprotein E status. Multiple comparisons were corrected for using the false discovery rate.Results: The homozygous major allele of rs2298813 was associated with larger volumes in the right putamen (p = 0.0442) and right pallidum (p = 0.0346). There was no link between the rs1784933 genotypes with any regional volume or thickness of the brain. In the rs2298813 homozygous major allele carriers, the right putaminal volume was associated with verbal fluency (p = 0.008), and both the right putaminal and pallidal volumes were predictive of clinical progression at follow-up (p = 0.020). In the minor allele carriers, neither of the nuclei was related to cognitive test performance or clinical progression.Conclusion: The major and minor alleles of rs2298813 had differential effects on the right lentiform nucleus volume and distinctively modulated the association between the regional volume and cognitive function in patients with AD.

Abstract Background Chronic headache may persist after the remission of reversible cerebral vasoconstriction syndrome (RCVS) in some patients. We aimed to investigate the prevalence, characteristics, risk factors, and the impact of post-RCVS headache. Methods We prospectively recruited patients with RCVS and collected their baseline demographics, including psychological distress measured by Hospital Anxiety and Depression scale. We evaluated whether the patients developed post-RCVS headache 3 months after RCVS onset. The manifestations of post-RCVS headache and headache-related disability measured by Migraine Disability Assessment (MIDAS) scores were recorded. Results From 2017 to 2019, 134 patients with RCVS were recruited, of whom, 123 finished follow-up interviews (response rate 91.8%). Sixty (48.8%) patients had post-RCVS headache. Migrainous features were common in post-RCVS headache. Post-RCVS headache caused moderate-to-severe headache-related disability (MIDAS score > 10) in seven (11.7%) patients. Higher anxiety level (odds ratio 1.21, p = 0.009) and a history of migraine (odds ratio 2.59, p = 0.049) are associated with post-RCVS headache. Survival analysis estimated that 50% post-RCVS headache would recover in 389 days (95% confidence interval: 198.5–579) after disease onset. Conclusions Post-RCVS headache is common, affecting half of patients and being disabling in one-tenth. Higher anxiety level and migraine history are risk factors. Half of the patients with post-RCVS headache would recover in about a year.

Abstract Dementia is related to the cellular accumulation of β-amyloid plaques, tau aggregates, or α-synuclein aggregates, or to neurotransmitter deficiencies in the dopaminergic and cholinergic pathways. Cellular and neurochemical changes are both involved in dementia pathology. However, the role of dopaminergic and cholinergic networks in metabolic connectivity at different stages of dementia remains unclear. The altered network organisation of the human brain characteristic of many neuropsychiatric and neurodegenerative disorders can be detected using persistent homology network (PHN) analysis and algebraic topology. We used 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging data to construct dopaminergic and cholinergic metabolism networks, and used PHN analysis to track the evolution of these networks in patients with different stages of dementia. The sums of the network distances revealed significant differences between the network connectivity evident in the Alzheimer’s disease and mild cognitive impairment cohorts. A larger distance between brain regions can indicate poorer efficiency in the integration of information. PHN analysis revealed the structural properties of and changes in the dopaminergic and cholinergic metabolism networks in patients with different stages of dementia at a range of thresholds. This method was thus able to identify dysregulation of dopaminergic and cholinergic networks in the pathology of dementia.

Abstract Background Dementia in the oldest-old is projected to increase exponentially as is the burden of their caregivers who may experience unique challenges and suffering. Thus, we aim to investigate which factors are associated with older caregivers’ burden in caring demented outpatients in a multicenter cohort. Methods Patients and their caregivers, both aged ≧65 years, in the National Dementia Registry Study in Taiwan (T-NDRS) were included in this study. Caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The correlations between the ZBI scores and characteristics of caregivers and patients, including severity of dementia, physical comorbidities, instrumental activities of daily living (IADL), neuropsychiatric symptoms assessed by the Neuropsychiatric Inventory (NPI), and family monthly income, were analyzed. Results We recruited 328 aged informal caregiver-patient dyads. The mean age of caregivers was 73.7 ± 7.0 years, with female predominance (66.8%), and the mean age of patients was 78.8 ± 6.9 years, with male predominance (61.0%). Multivariable linear regression showed that IADLs (β = 0.83, p

BackgroundTranscranial direct current stimulation (tDCS) is a non-invasive brain stimulation to modulate cortical activity for improving motor function. However, the information of tDCS stimulation on different brain regions for dual-task walking and cortical modulation in Parkinson’s disease (PD) has not yet been compared.ObjectiveThe objective of this study was to investigate the effects of different tDCS targets on dual-task gait performance and cortical activity in patients with PD.MethodsA total of 36 participants were randomly assigned to primary motor cortex (M1) tDCS, dorsal lateral prefrontal cortex (DLPFC) tDCS, cerebellum tDCS, or Sham tDCS group. Each group received 20 min of tDCS stimulation, except for the Sham group. Gait performance was measured by the GAITRite system during dual-task walking and single walking. Corticomotor activity of the tibialis anterior (TA) was measured using transcranial magnetic stimulation (TMS). The functional mobility was assessed using the timed up and go (TUG) test.ResultsAll participants showed no significant differences in baseline data. Following the one session of tDCS intervention, M1 (p = 0.048), DLPFC (p < 0.001), and cerebellum (p = 0.001) tDCS groups demonstrated significant improvements in dual-task gait speed compared with a pretest. The time × group interaction [F(3, 32) = 5.125, p = 0.005] was detected in dual-task walking speed. The post hoc Tukey’s test showed that the differences in gait speed were between the Sham tDCS group and the DLPFC tDCS group (p = 0.03). Moreover, DLPFC tDCS also increased the silent period (SP) more than M1 tDCS (p = 0.006) and Sham tDCS (p = 0.002).ConclusionThe results indicate that DLPFC tDCS exerted the most beneficial effects on dual-task walking and cortical modulation in participants with PD.Clinical trial registration[http://www.thaiclinicaltrials.org/show/TCTR20200909005], Thai Clinical Trials Registry [TCTR20200909005].

Objective: Lower serum low-density lipoprotein cholesterol (LDL-C) levels are associated with increased intracerebral hemorrhage (ICH) risk. However, reverse causality and residual confounding has not attracted public attention. Therefore, we assessed whether people with LDL-C have increased risk of mortality adjusting for potential confounders using two large Taiwan cohorts.Methods: The Mei-Jhao (MJ) cohort has 414,372 adults participating in a medical screening program with 378 ICH deaths within 15 years of follow-up (1994–2008). Cox proportional hazards regressions estimated hazard death ratios according to LDL-C levels. We identified 4,606 ICH patients from the Taiwan Stroke Registry (TSR) and analyzed the impact of LDL-C on 3-month mortality.Results: Low cholesterol (LDL-C

Background: There has been an increasing interest in studying electroencephalogram (EEG) as a biomarker of Alzheimer’s disease but the association between EEG signals and patients’ neuropsychiatric symptoms remains unclear. We studied EEG signals of patients with Alzheimer’s disease to explore the associations between patients’ neuropsychiatric symptoms and clusters of patients based on their EEG powers.Methods: A total of 69 patients with mild Alzheimer’s disease (the Clinical Dementia Rating = 1) were enrolled and their EEG signals from 19 channels/electrodes were recorded in three sessions for each patient. The EEG power was calculated by Fourier transform for the four frequency bands (beta: 13–40 Hz, alpha: 8–13 Hz, theta: 4–8 Hz, and delta:

Abstract Background Limited histopathology studies have suggested that reversible cerebral vasoconstriction syndromes (RCVS) does not present with vascular wall inflammation. Previous vascular imaging studies have had inconsistent vascular wall enhancement findings in RCVS patients. The aim of this study was to determine whether absence of arterial wall pathology on imaging is a universal finding in patients with RCVS. Methods We recruited patients with RCVS from Taipei Veterans General Hospital prospectively from 2010 to 2012, with follow-up until 2017 (n = 48). We analyzed the characteristics of vascular wall enhancement in these patients without comparisons to a control group. All participants received vascular wall imaging by contrasted T1 fluid-attenuated inversion recovery with a 3-T magnetic resonance machine. The vascular wall enhancement was rated as marked, mild or absent. Results Of 48 patients with RCVS, 22 (45.8%) had vascular wall enhancement (5 marked and 17 mild). Demographics, clinical profiles, and cerebral artery flow velocities were similar across patients with versus without vascular wall enhancement, except that patients with vascular wall enhancement had fewer headache attacks than those without (p = 0.04). Follow-up imaging completed in 14 patients (median interval, 7 months) showed reduced enhancement in 9 patients, but persistent enhancement in 5. Conclusion Almost half of our RCVS patients exhibited imaging enhancement of diseased vessels, and it was persistent for approximately a third of those patients with follow-up imaging. Both acute and persistent vascular wall enhancement may be unhelpful for differentiating RCVS from central nervous system vasculitis or subclinical atherosclerosis.

Abstract Monocyte chemoattractant protein-1 (MCP-1, also known as chemokine CCL2) is a vital chemokine that mediates inflammation in Alzheimer’s disease (AD). We analyzed the associations between the baseline plasma MCP-1 level, longitudinal cognitive changes, and genetic effects of CCL2 rs1024611 and its receptor, CC-chemokine receptor 2 (CCR2) rs1799864, in AD. In total, 310 AD patients and 66 mild cognitive impairment (MCI) patients were followed for 2 years, and 120 controls were recruited at baseline for comparison. After adjusting for covariates using one-way analysis of covariance, AD patients had higher plasma MCP-1 levels compared with MCI patients and controls, and severe AD patients had the highest levels. After adjusting for covariates using generalized estimating equation analysis, the results showed that the baseline MCP-1 level was significantly correlated with changes in the two-year Mini-Mental Status Examination (p = 0.046). The A allele of CCR2 rs1799864 was associated with a higher MCP-1 level in AD and MCI patients. In conclusion, plasma MCP-1 might reflect the risk and disease course of AD. A higher plasma MCP-1 level is associated with greater severity and faster cognitive decline. Additionally, the CCR2 polymorphism may play a role in the regulation of MCP-1/CCR2 signaling in AD.

Abstract Background Despite evidently distinct symptoms, tension-type headache (TTH) and migraine are highly comorbid and exhibit many similarities in clinical practice. The purpose of this study was to investigate whether both types of headaches are similar in brain morphology. Methods Consecutive patients with TTH and age- and sex-matched patients with migraine and healthy controls were enrolled for brain magnetic resonance imaging examination. Patients with TTH were excluded if they reported any headache features or associated symptoms of migraine. Changes in gray matter (GM) volume associated with headache diagnosis (TTH vs. migraine) and frequency (episodic vs. chronic) were examined using voxel-based morphometry. The correlation with headache profile and the discriminative ability between TTH and migraine were also investigated for these GM changes. Results In comparison with controls (n = 43), the patients with TTH (25 episodic and 24 chronic) exhibited a GM volume increase in the anterior cingulate cortex, supramarginal gyrus, temporal pole, lateral occipital cortex, and caudate. The patients with migraine (31 episodic and 25 chronic) conversely exhibited a GM volume decrease in the orbitofrontal cortex. These GM changes did not correlate with any headache profile. A voxel-wise 2 × 2 factorial analysis further revealed the substantial effects of headache types and frequency in the comparison of GM volume between TTH and migraine. Specifically, the migraine group (vs. TTH) had a GM decrease in the superior and middle frontal gyri, cerebellum, dorsal striatum, and precuneus. The chronic group (vs. episodic group) otherwise demonstrated a GM decrease in the bilateral insula and anterior cingulate cortex. In receiver operating characteristic analysis, the GM volumes of the left superior frontal gyrus and right cerebellum V combined had good discriminative ability for distinguishing TTH and migraine (area under the curve = 0.806). Conclusions TTH and migraine are separate headache disorders with different characteristics in relation to GM changes. The major morphological difference between the two types of headaches is the relative GM decrease of the prefrontal and cerebellar regions in migraine, which may reflect a higher allostatic load associated with this disabling headache.

Abstract Background Clusterin and beta-amyloid (Aβ) are involved in the pathogenesis of Alzheimer’s disease (AD). The clinical significance of plasma clusterin and Aβ in AD progression remains controversial. Methods We recruited 322 patients with AD and 88 controls between August 2012 and June 2013. All participants were evaluated at baseline with a clinical assessment, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR) scales. Patients with AD were evaluated annually with the MMSE and Neuropsychiatric Inventory (NPI) scale during the 2-year follow-up period. The levels of plasma clusterin, Aβ1–40, and Aβ1–42 at baseline were analyzed to study the longitudinal changes in the patient scores on the MMSE and NPI during the follow-up period. Results Patients in the highest tertile of plasma clusterin levels showed significantly lower MMSE scores than those in the lowest tertile (p = 0.04). After adjustment for multiple covariates using the generalized estimating equation analysis, there was a significant decrease in the MMSE scores over the 2-year follow-up period among AD patients in the highest tertile of plasma clusterin levels compared with those in the lowest tertile (−2.09, 95% confidence interval (CI) = −3.67 to −0.51, p = 0.01). In apolipoprotein E (ApoE)4-positive AD patients, baseline measurements of the ratio of plasma Aβ1–42/Aβ1–40 in the highest tertile predicted an increase in NPI agitation/aggression scores over the 2-year follow-up period (6.06, 95% CI = 1.20–10.62, p = 0.02). Conclusions Plasma clusterin could serve as a biomarker for the severity of cognitive decline. Plasma Aβ in ApoE4-positive AD could predict long-term agitation/aggression symptoms.

Abstract This study investigated the relationships among plasma biomarkers, regional brain atrophy, and clinical symptoms in patients with Alzheimer’s disease (AD; n = 177), mild cognitive impairment (MCI; N = 60) and controls (n = 108). The Mini-Mental Status Examination (MMSE), Clinical Dementia Rating (CDR), and Neuropsychiatric Inventory (NPI) subscales were administered to subjects. Magnetic resonance imaging was performed and medial temporal atrophy (MTA) and posterior atrophy (PA) were assessed visually. We examined associations among cognition, NPI score, plasma β-amyloid (Aβ) and clusterin levels, and regional brain atrophy in patients with AD by regression analysis. The mean MTA score was associated with the plasma Aβ1-42/Aβ1-40 ratio (r = 0.38, p = 0.01) and with MMSE scores (r = 0.43, p

Alzheimer's disease (AD) is a progressive brain disorder with gradual memory loss that correlates to cognitive deficits in the elderly population. Recent studies have shown the potentials of machine learning algorithms to identify biomarkers and functional brain activity patterns across various AD stages using electroencephalography (EEG). In this study, we aim to discover the altered spatio-temporal patterns of EEG complexity associated with AD pathology in different severity levels. We employed the multiscale entropy (MSE), a complexity measure of time series signals, as the biomarkers to characterize the nonlinear complexity at multiple temporal scales. Two regularized logistic regression methods were applied to extracted MSE features to capture the topographic pattern of MSEs of AD cohorts compared to healthy baseline. Furthermore, canonical correlation analysis was performed to evaluate the multivariate correlation between EEG complexity and cognitive dysfunction measured by the Neuropsychiatric Inventory scores. 123 participants were recruited and each participant was examined in three sessions (length = 10 seconds) to collect resting-state EEG signals. MSE features were extracted across 20 time scale factors with pre-determined parameters (m = 2, r = 0.15). The results showed that comparing to logistic regression model, the regularized learning methods performed better for discriminating severe AD cohort from normal control, very mild and mild cohorts (test accuracy ~ 80%), as well as for selecting significant biomarkers arcoss the brain regions. It was found that temporal and occipitoparietal brain regions were more discriminative in regard to classifying severe AD cohort vs. normal controls, but more diverse and distributed patterns of EEG complexity in the brain were exhibited across individuals in early stages of AD.

BackgroundMigraine is frequently comorbid with restless legs syndrome (RLS), both displaying functional connectivity (FC) alterations in multiple brain networks, although the neurological basis of this association is unknown.MethodsWe performed resting-state functional magnetic resonance imaging and network-wise analysis of FC in migraine patients with and without RLS and healthy controls (CRL). Network-based statistics (NBS) and composite FC matrix analyses were performed to identify the patterns of FC changes. Correlation analyses were performed to identify associations between alterations in FC and clinical profiles.ResultsNBS results revealed that both migraine patients with and without RLS exhibited lower FC than CRL in the dorsal attention, salience, default mode, cingulo-opercular, visual, frontoparietal, auditory, and sensory/somatomotor networks. Further composite FC matrix analyses revealed differences in FC of the salience, default mode to subcortical and frontoparietal, auditory to salience, and memory retrieval networks between migraine patients with and without RLS. There was a trend toward a negative association between RLS severity and cross-network abnormalities in the default mode to subcortical network.DiscussionMigraine patients with and without RLS exhibit disruptions of brain FC. Such findings suggest that these disorders are associated with differential neuropathological mechanisms and may aid in the future development of neuroimaging-driven biomarkers for these conditions.

Objective: To assess the factors associated with future pregnancy and successful delivery in women who were treated for uterine adenomyoma with combination (surgical–medical) therapy using ultramini- or mini-laparotomy conservative surgery and gonadotropin-releasing hormone agonist. Materials and Methods: One hundred and two women were evaluated. Items for analysis included: age, body mass index, and conception history; clinical symptoms of dysmenorrhea and menorrhagia; tumor location and preoperative serum level of cancer antigen 125 (CA125); the intraoperative findings of the weight of the removed tumor, and the uterine cavity opening. Results: After excluding those patients using contraception or searching for an assisted reproductive technique, a total of 56 women were enrolled for analysis. Twenty-three (41.1%) women had 27 clinical pregnancies after 3 years of follow-up; 15 went on to deliver a healthy live-born child; two delivered preterm but healthy babies; seven had elective abortions; four had spontaneous abortions; and one had an ectopic pregnancy. The women who had a successful delivery during the 3-year follow-up after treatment tended to be younger, with a lower body mass index, lower baseline analgesic usage score, and lower preoperative serum level of CA125, be nulliparous, and with an adenoma in an anterior location. The linear regression model showed that age and baseline analgesic usage score were independent predictors of successful delivery and accounted for 56.5% of the total variance related to successful delivery. Conclusion: Age was an important factor associated with future successful delivery, therefore, caution should be taken in considering the maintenance of future fertility in older women treated with surgical–medical therapy.