Comparative effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies and onabotulinumtoxinA in chronic migraine: A multicenter, real-world study in Taiwan.

OBJECTIVE: To compare the real-world effectiveness and tolerability of calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) and onabotulinumtoxinA in chronic migraine (CM) patients. METHODS: This multicenter study involved retrospective analysis of prospectively collected data of CM patients treated with CGRP mAbs or onabotulinumtoxinA, including difficult-to-treat (DTT) patients (i.e., ≥3 preventive failures). Treatment outcomes were determined at 6 months based on prospective headache diaries and Migraine Disability Assessment (MIDAS). RESULTS: The study included 316 (55 M/261F, mean age 44.4 ± 13.5 years) and 333 (61 M/272F, mean age 47.9 ± 13.4 years) CM patients treated with CGRP mAbs or onabotulinbumtoxinA, respectively. At 6 months, CGRP mAb treatment was associated with a greater decrease in monthly migraine days (MMDs) (-13.0 vs. -8.7 days/month, p < 0.001) and a higher ≥50% responder rate (RR) (74.7% vs. 50.7%, p < 0.001) compared with onabotulinumtoxinA injections. The findings were consistent in DTT patients (-13.0 vs. -9.1 MMDs, p < 0.001; ≥50% RR: 73.9% vs. 50.3%, p < 0.001) or those with medication-overuse headache (MOH) (-13.3 vs. -9.0 MMDs, p < 0.001; ≥50% RR: 79.0% vs. 51.6%, p < 0.001). Besides, patients receiving CGRP mAbs had greater improvement (-42.2 vs. -11.8, p < 0.001) and a higher ≥50% RR (62.0% vs. 40.0%, p = 0.001) in MIDAS scores and a lower rate of adverse events (AEs) (6.0% vs. 21.0%, p < 0.001). However, none of the patients discontinued treatment due to AEs. CONCLUSIONS: In this multicenter, real-world study, CGRP mAbs were more effective than onabotulinumtoxinA in CM patients, even in DTT or MOH patients. All of these injectables were well tolerated. Further prospective studies are needed to verify these findings.

Cerebrospinal Fluid Proteome Map Reveals Molecular Signatures of Reversible Cerebral Vasoconstriction Syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) is a complex neurovascular disorder characterized by repetitive thunderclap headaches and reversible cerebral vasoconstriction. The pathophysiological mechanism of this mysterious syndrome remains under-explored and there is no clinically available molecular biomarker. To provide insight into the pathogenesis of RCVS, this study reported the first landscape of dysregulated proteome of cerebrospinal fluid (CSF) in patients with RCVS (n = 21) compared to the age- and sex-matched controls (n = 20) using data-independent acquisition mass spectrometry (DIA-MS). Protein-protein interaction and functional enrichment analysis were employed to construct functional protein networks using the RCVS proteome. An RCVS-CSF proteome library resource of 1,054 proteins was established, which illuminated large groups of upregulated proteins enriched in the brain and blood-brain barrier (BBB). Personalized RCVS-CSF proteomic profiles from 17 RCVS patients and 20 controls reveal proteomic changes involving the complement system, adhesion molecules, and extracellular matrix, which may contribute to the disruption of BBB and dysregulation of neurovascular units. Moreover, an additional validation cohort validated a panel of biomarker candidates and a two-protein signature predicted by machine learning model to discriminate RCVS patients from controls with an area under the curve of 0.997. This study reveals the first RCVS proteome and a potential pathogenetic mechanism of BBB and neurovascular unit dysfunction. It also nominates potential biomarker candidates that are mechanistically plausible for RCVS, which may offer potential diagnostic and therapeutic opportunities beyond the clinical manifestations.

Different Splice Isoforms of Peripheral Triggering Receptor Expressed on Myeloid Cells 2 mRNA Expressions are Associated With Cognitive Decline in Mild Dementia Due to Alzheimer's Disease and Reflect Central Neuroinflammation.

Triggering receptor expressed on myeloid cells 2 (TREM2) is upregulated in activated microglia and may be related to cognitive decline in patients with Alzheimer's disease (AD). There is conflicting evidence regarding the association of peripheral TREM2 mRNA expression/soluble TREM2 (the extracellular domain of TREM2) with cognitive function/neuroinflammation in patients with AD. Herein, we studied the TREM2 and TREM2alt mRNA expression and their association with the cognitive performance in subjects with mild dementia due to AD and healthy controls. In a subgroup of patients with AD, magnetic resonance spectroscopy was used to measure the myo-inositol level in the posterior cingulate cortex, a surrogate marker for neuroinflammation. The results showed that increased TREM2 and TREM2alt mRNA expression is associated with AD pathogenesis at the mild dementia stage, thereby serving as a potential biomarker for early symptomatic stage of AD. TREM2 may exert protective effects on both cognition and central neuroinflammation.

Dynamic changes in glymphatic function in reversible cerebral vasoconstriction syndrome.

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 < 0.001) and remission RCVS (p < 0.001). A continuously increasing DTI-ALPS trend after disease onset was demonstrated. The DTI-ALPS was lower when the internal carotid arteries resistance index and six-item Headache Impact test scores were higher. In contrast, during 50-100 days after disease onset, the DTI-ALPS index was higher when the middle cerebral artery flow velocity was higher. CONCLUSIONS: Glymphatic function in patients with RCVS exhibited a unique dynamic evolution that was temporally coupled to different vascular indices and headache-related disabilities along the disease course. These findings may provide novel insights into the complex interactions between glymphatic transport, vasomotor control and pain modulation.

Predictors of live-in migrant caregiver employment for people with dementia in Taiwan.

BACKGROUND: With the increasing number of individuals with dementia, families have hired an increasing number of live-in migrant caregivers (LIMCs). Currently, limited evidence is available regarding the influence of long-term care resource utilization on the hiring of LIMCs for caring for individuals with dementia in Taiwan. METHODS: We recruited individuals with dementia who did not hire LIMCs and their primary family caregivers from nine hospitals in Taiwan as baseline. Multivariable logistic regression was used to evaluate the utilization of long-term care resources for individuals with dementia and other factors that may affect the decision to hire LIMCs. RESULTS: The users of non-long-term care resources had the highest likelihood of hiring LIMCs (odds ratio [OR] = 4.24, 95% CI, 2.30-7.84). Compared with spouses, nonimmediate family caregivers (OR = 3.40, 95% CI, 1.16-9.90) were significantly more likely to hire LIMCs. A higher likelihood of hiring LIMCs was observed for those with Lewy body dementia compared with other individuals (OR = 2.31, 95% CI, 1.03-5.14). Compared with individuals who did not hire LIMCs, those who hired LIMCs exhibited higher scores on the Neuropsychiatric Inventory (NPI) and higher severity of individual NPI items. CONCLUSION: Hiring LIMCs is strongly correlated with the utilization of non-long-term care resources and is influenced by the dynamics between individuals with dementia and their primary family caregivers. A higher likelihood of hiring LIMCs was observed for individuals with Lewy body dementia and individuals with elevated NPI scores compared with their counterparts. Given these observations, various support strategies and interventions should be tailored to the specific requirements of individuals with dementia and their families.

Application of blood-based biomarkers of Alzheimer's disease in clinical practice: Recommendations from Taiwan Dementia Society.

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 Aß42/Aß40 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.

Are demographic factors, masticatory performance and structural brain signatures associated with cognitive impairment in older people? A pilot study of cross-sectional neuroimaging data.

BACKGROUND: The occurrence of cognitive impairment (CI) is expected to increase within an ageing population. CI is associated with tooth loss, which influences masticatory performance. A decrease in masticatory performance may cause functional and morphological changes in the brain. However, whether CI is associated with masticatory performance, demographics, and structural brain signatures has not been studied yet. OBJECTIVES: To assess the associations between CI on the one hand, and masticatory performance, demographic factors, and structural brain signatures (i.e. cortical volume and thickness) on the other hand. METHODS: In total, 18 older adults with CI (mean ± SD age = 72.2 ± 9.5 years) and 68 older adults without CI (65.7 ± 7.5 years) were included in this study. Masticatory performance was quantified using a colour-changeable chewing gum. A Magnetic Resonance Imaging (MRI) scan was used to map structural brain signatures. To study our aim, a multivariate binary logistic regression analysis with backward selection was performed. RESULTS: The cortical volume of the right entorhinal cortex was negatively associated with CI (p < .01). However, demographic factors, masticatory performance, and the other structural brain signatures under investigation were not associated with CI. CONCLUSION: A decrease in the volume of the right entorhinal cortex is associated with CI in older people.

An umbrella review on the association between factors of oral health and cognitive dysfunction.

An increasing number of systematic reviews and meta-analyses have been published on the association between oral health and cognitive dysfunction, also known as oral-cognitive links. However, there is great diversity in the oral and cognitive factors included in these studies, with different opinions for clinical practice drawn from the evidence. To understand which oral and cognitive factors are involved in those associations, we conducted an umbrella review of 28 systematic reviews, including 12 meta-analyses, on oral-cognitive links. We found that (a) periodontal diseases, oral microbiome, and dementia were frequently studied, while other factors, such as mastication and mild cognitive impairment, were less commonly investigated, and (b) severe deterioration of oral health, such as severe periodontitis or extensive tooth loss, rather than the presence of oral diseases alone, was strongly associated with cognitive dysfunction. In conclusion, the diversity of oral and cognitive factors included in the review studies reflects the complexity of oral-cognitive links. Clarifying the factors helps to form evidence-based clinical advice for healthcare.

A national survey on health-related quality of life for people with dementia in residential long-term care institutions.

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.

Association between impaired dynamic cerebral autoregulation and BBB disruption in reversible cerebral vasoconstriction syndrome.

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.

A holo-spectral EEG analysis provides an early detection of cognitive decline and predicts the progression to Alzheimer's disease.

Aims: Our 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. Methods: A 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. Conclusion: Integrating 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.

Serum brain-derived neurotrophic factor levels as a predictor for Alzheimer disease progression.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of Alzheimer's disease (AD), and decreased peripheral levels of this protein are associated with an increased risk of developing the disease. This study focuses on whether serum BDNF levels could be used as a predictor of AD progression. METHODS: In this longitudinal observational study, we recruited cognition normal participants (N = 98) and AD (N = 442) from the Clinic at the Taipei Veterans General Hospital. We conducted a mini-mental status exam, a 12-item memory test, a categorical verbal fluency test, and a modified 15-item Boston naming test. A Serum BDNF level and apolipoprotein E ( APOE ) allele status were measured. The AD patients were followed prospectively. Based on the difference of MMSE scores, these patients were divided into fast decliners (decline ≥ 3/y) and slow decliners (MMSE decline < 3/y). Logistic regression was conducted to examine the impact of serum BDNF levels and other factor on the likelihood of AD patients being slow decliners. Pearson's correlation was used to estimate the relationship between serum BDNF levels and the score of neuropsychological tests. RESULTS: In a logistic regression model containing serum BDNF levels, age, sex, APOE4 carrier status, education levels, and baseline MMSE score, higher serum BDNF levels were associated with a slower rate of cognitive decline in the AD group. Serum BDNF levels positively correlated with the results of multiple neuropsychological tests. CONCLUSION: BDNF is a protective factor against AD progression and likely plays a role in establishing a link between AD pathology and clinical manifestations.

Health-related quality of life and mild behavioral impairment in older adults without dementia.

BACKGROUND: The Mild Behavioral Impairment Checklist (MBI-C) was developed to assess neuropsychiatric symptoms (NPS) and to identify mild behavioral impairment (MBI). This study validated the Taiwanese version of the MBI-C and examined its association of health-related quality of life (HR-QoL). METHODS: We recruited 242 older individuals without dementia (129 amnestic mild cognitive impairment, 113 cognitively normal). Their family completed the MBI-C, the Neuropsychiatric Inventory Questionnaire (NPI-Q), and instrumental activities of daily living scale. Participants completed the Geriatric Depression Scale (GDS-15), the Mini-Mental State Examination, the 12-item word recall test, the category verbal fluency test and the EuroQol 5 dimensions questionnaire (EQ-5D). Cronbach's α was used to evaluate the internal consistency of the MBI-C. Linear regression models were used to examined the association between MBI-C score and HR-QoL assessed using ED-5D. RESULTS: The prevalence of MBI was 12% of all participants. Cronbach's α of the MBI-C was 0.893. The optimal cut-off point of MBI-C was 7.5 for identifying MBI, with a sensitivity of 100% and specificity of 85%. The MBI-C total score (ß = -0.01, 95% confidence interval [CI] = -0.02 to -0.01, p < 0.001), MBI-C subdomain of decreased motivation (ß = -0.04, 95% CI = -0.05 to -0.02, p < 0.001) and emotional dysregulation (ß = -0.02, 95% CI = -0.04 to -0.004, p = 0.01) were factors related to EQ-5D index scores. CONCLUSION: Among older adults without dementia, the Taiwanese version of the MBI-C has good reliability and validity for detecting MBI. The total and subdomains of MBI-C were associated with decreased HR-QoL among individuals without dementia.

Feasibility evaluation of middle-phase 18F-florbetaben positron emission tomography imaging using centiloid quantification and visual assessment.

Background: 18F-florbetaben (FBB) positron emission tomography (PET) scan has been widely used in research and routine clinical practice. Most studies used late-phase (scanning from 90 to 110 min after injection) FBB scans to generate beta-amyloid accumulation data. The feasibility of middle-phase scan is seldom discussed. Using the middle-phase data can shorten the patients' waiting between the injection and scan, and hospital can acquire more flexible schedule of routine scan. Methods: Paired middle-phase (60-80 min) FBB scans and standard (90-110 min) FBB scans were obtained from 27 subjects (12 neurodegenerative dementia, 8 mild cognitive impairment, 3 normal control, and 4 patients not suffering from neurodegenerative dementia). Standardized uptake value ratios (SUVRs) were calculated and converted to centiloid (CL) scale to investigate the impact on image quantification. CL pipeline validation were performed to build an equation converting the middle-phase data into equivalent standard scans. Cohen's kappa of binary interpretation and brain amyloid plaque load (BAPL) score were also used to evaluate the intrareader agreement of the FBB image from the two protocols. Results: The middle-phase FBB SUVR showed an excellent correlation, which provided a linear regression equation of SUVRFBB60-80 = 0.88 × SUVRFBB90-110 + 0.07, with R2=0.98. The slope of the equation indicated that there was bias between the middle and standard acquisition. This can be converted into the CL scale using CL = 174.68 × SUVR - 166.39. Cohen's kappa of binary interpretation and BAPL score were 1.0 (P<0.0001). Conclusions: Our findings indicate that the middle-phase FBB protocol is feasible in clinical applications for scans that are at either end of beta-amyloid spectrum, which provides comparable semiquantitative results to standard scan. Patient's waiting time between the injection and scan can be shortened.

Noninvasive investigations of human glymphatic dynamics in a diseased model.

OBJECTIVES: To explore human glymphatic dynamics in a diseased model via a noninvasive technique. METHODS: Patients with reversible vasoconstriction syndrome (RCVS) presenting with blood-brain barrier disruption, i.e., para-arterial gadolinium leakage on 3-T 3-dimensional isotropic contrast-enhanced T2-fluid-attenuated inversion recovery (CE-T2-FLAIR) magnetic resonance imaging (MRI), were prospectively enrolled. Consecutive 9-min-CE-T2-FLAIR for 5-6 times (early panel) after intravenous gadolinium-based contrast agent (GBCA) administration and one time-varying deferred scan of noncontrast T2-FLAIR (delayed panel) were performed. In Bundle 1, we measured the calibrated signal intensities (cSIs) of 10 different anatomical locations. In Bundle 2, brain-wide measurements of para-arterial glymphatic volumes, means, and medians of the signal intensities were conducted. We defined mean (mCoIs) or median (mnCoIs) concentration indices as products of volumes and signal intensities. RESULTS: Eleven subjects were analyzed. The cSIs demonstrated early increase (9 min) in perineural spaces: (cranial nerve [CN] V, p = 0.008; CN VII + VII, p = 0.003), choroid plexus (p = 0.003), white matter (p = 0.004) and parasagittal dura (p = 0.004). The volumes, mCoIs, and mnCoIs demonstrated increasing rates of enhancement after 9 to 18 min and decreasing rates after 45 to 54 min. The GBCA was transported centrifugally and completely removed within 961-1086 min after administration. CONCLUSIONS: The exogenous GBCA leaked into the para-arterial glymphatics could be completely cleared around 961 to 1086 min after administration in a human model of BBB disruption. The tracer enhancement started variously in different intracranial regions but was eventually cleared centrifugally to brain convexity, probably towards glymphatic-meningeal lymphatics exits. CLINICAL RELEVANCE STATEMENT: Glymphatic clearance time intervals and the centrifugal directions assessed by a noninvasive approach may have implications for clinical glymphatic evaluation in the near future. KEY POINTS: • This study aimed to investigate the human glymphatic dynamics in a noninvasive diseased model. • The intracranial MR-detectable gadolinium-based contrast agents were removed centrifugally within 961 to 1086 min. • The glymphatic dynamics was demonstrable by enhancing MRI in an in vivo diseased model noninvasively.

Disrupted Brain Functional Status in Patients with Reversible Cerebral Vasoconstriction Syndrome.

OBJECTIVES: The aim of this study was to investigate the functional networks in subjects with reversible cerebral vasoconstriction syndrome (RCVS) using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: We prospectively recruited patients with RCVS and healthy controls (HCs) between February 2017 and April 2021. The rs-fMRI data were analyzed using graph theory methods. We compared node-based global and regional topological metrics (Bundle 1) and network-based intranetwork and internetwork connectivity (Bundle 2) between RCVS patients and HCs. We also explored the associations of clinical and vascular (ie, the Lindegaard index, LI) parameters with significant rs-fMRI metrics. RESULTS: A total of 104 RCVS patients and 93 HCs were included in the final analysis. We identified significantly decreased local efficiency of the left dorsal anterior insula (dAI; p = 0.0005) in RCVS patients within 30 days after disease onset as compared to HCs, which improved 1 month later. RCVS patients also had increased global efficiency (p = 0.009) and decreased average degree centrality (p = 0.045), clustering coefficient (p = 0.033), and assortativity values (p = 0.003) in node-based analysis. In addition, patients with RCVS had increased internetwork connectivity of the default mode network (DMN) with the salience (p = 0.027) and dorsal attention (p = 0.016) networks. Significant correlations between LI and regional local efficiency in left dAI (rs = -0.418, p = 0.042) was demonstrated. INTERPRETATION: The significantly lower local efficiency of the left dAI, suggestive of impaired central autonomic modulation, was negatively correlated with vasoconstriction severity, which is highly plausible for the pathogenesis of RCVS. ANN NEUROL 2023;94:772-784.

Association between masseter muscle volume, nutritional status, and cognitive status in older people.

OBJECTIVES: Clinical evidence has suggested that oral function is associated with cognitive, physical, and nutritional status of older people. A smaller volume of masseter, a crucial muscle for mastication, was associated with frailty. It has remained unknown if smaller masseter is associated with cognitive impairment. The current study investigated the association between masseter muscle volume, nutritional status, and cognitive status in older people. MATERIALS AND METHODS: We recruited 19 patients with mild cognitive impairment (MCI), 15 patients with Alzheimer's disease (AD), and 28 sex and age-matched non-cognitive impairment (non-CI) older subjects. The number of missing teeth (NMT), masticatory performance (MP), maximal hand-grip force (MGF), and calf circumference (CC) were assessed. The masseter volume index (MVI) was calculated based on the masseter volume measured using magnetic resonance imaging. RESULTS: The MVI was significantly lower in the AD group, compared to the MCI as well as the non-CI group. Multiple regression analyses revealed that the MVI was significantly associated with nutritional status (as indexed by CC) in the analysis of combination of NMT, MP, and the MVI. Moreover, the MVI was a significant predictor of CC only in patients with cognitive impairment (i.e., MCI+AD) but not in the non-CI group. CONCLUSIONS: Our findings suggested that in addition to the NMT and MP, masseter volume is a critical oral factor associated with cognitive impairment. CLINICAL RELEVANCE: Reduction of MVI should be carefully monitored for patients with dementia and frailty, to whom a lower MVI may indicate worse nutrient intake.

Transient visual disturbances are associated with disability and suicide risk in patients with migraine without aura.

BACKGROUND: To investigate the characteristics and clinical correlates of transient visual disturbances (TVDs) in patients with migraine without aura (MO). Patients with MO frequently report TVDs, which differ from typical visual aura, but the clinical significance of these TVDs has not been determined. METHODS: Patients with MO who attended our headache clinics were enrolled. Structured questionnaires were used to acquire data on participants' headache profiles, disability, comorbidities, and lifetime suicidal ideation and suicide attempts. A semistructured visual phenomenon questionnaire was used to characterize TVDs. Headache specialists interviewed the participants for diagnosis and the verification of questionnaire responses. RESULTS: Patients with MO (n = 7200; female/male ratio = 3.56, mean age 40.1 ± 13.4 years) were divided into two groups based on the presence (n = 2488) or absence (n = 4712) of TVDs. Patients with TVDs had more headache-related disability, psychiatric comorbidities, and photophobia than did those without TVDs. Suicidal ideation and suicide attempts were more common among patients with than among those without TVDs [ideation: odds ratio (OR) = 1.92, 95% confidence interval (CI) 1.71-2.15, p < 0.001; suicide attempt: OR = 2.23, 95% CI 1.80-2.75, p < 0.001]. CONCLUSION: The presence of TVDs may imply greater migraine-related disability, photophobia, and suicidal ideation/suicide attempt risk in patients with MO.

The SIH-EBP Score: A grading scale to predict the response to the first epidural blood patch in spontaneous intracranial hypotension.

BACKGROUND: To develop and validate an easy-to-use scoring system to predict the response to the first epidural blood patching in patients with spontaneous intracranial hypotension. METHODS: This study recruited consecutive patients with spontaneous intracranial hypotension receiving epidural blood patching in a tertiary medical center, which were chronologically divided into a derivation cohort and a validation cohort. In the derivation cohort, factors associated with the first epidural blood patching response were identified by using multivariable logistic regression modeling. A scoring system was developed, and the cutoff score was determined by using the receiver operating characteristic curve. The findings were verified in an independent validation cohort. RESULTS: The study involved 280 patients in the derivation cohort and 78 patients in the validation cohort. The spontaneous intracranial hypotension-epidural blood patching score (range 0-5) included two clinical variables (sex and age) and two radiological variables (midbrain-pons angle and anterior epidural cerebrospinal fluid collections). A score of ≥3 was predictive of the first epidural blood patching response, which was consistent in the validation cohort. Overall, patients who scored ≥3 were more likely to respond to the first epidural blood patching (odds ratio = 10.3). CONCLUSION: For patients with spontaneous intracranial hypotension-epidural blood patching score ≥3, it is prudent to attempt at least one targeted epidural blood patching before considering more invasive interventions.

Lower masticatory function relates to cognitive health and intrinsic brain network in older adults.

OBJECTIVES: Mastication is associated with brain activation at the primary somatosensory cortex (S1) and the primary motor cortex (M1). Masticatory functions differ between patients with cognitive impairment (CI) and cognitively healthy older adults (non-CI). The association between cognitive health, brain network of functional connectivity, and mastication has remained unknown. The study investigated the association between masticatory performance (MP) and the topological feature of the functional network at the M1 and S1 in the CI and non-CI groups. SUBJECTS AND METHODS: Forty-nine non-CI and 15 CI subjects received resting-state (rs) fMRI and assessment of MP. The topological feature of the M1 and S1 was quantified by eigenvector centrality (EC), an index that reflects a brain region as a functional "hub" of brain network. RESULTS: In the non-CI group, MP was significantly correlated with EC of the left M1 and the right M1. The correlation was not statistically significant in the CI group. Cognitive status (CI or non-CI) and EC of the left M1 and the right M1, respectively, were statistically significant predictors to individual MP. CONCLUSION: Cognitive status and the topological feature of the M1 in the intrinsic functional network may contribute to the individual difference in masticatory function.