Deep learning-regularized, single-step quantitative susceptibility mapping quantification.

The purpose of the current study was to develop deep learning-regularized, single-step quantitative susceptibility mapping (QSM) quantification, directly generating QSM from the total phase map. A deep learning-regularized, single-step QSM quantification model, named SS-POCSnet, was trained with datasets created using the QSM synthesis approach in QSM reconstruction challenge 2.0. In SS-POCSnet, a data fidelity term based on a single-step model was iteratively applied that combined the spherical mean value kernel and dipole model. Meanwhile, SS-POCSnet regularized susceptibility maps, avoiding underestimating susceptibility values. We evaluated the SS-POCSnet on 10 synthetic datasets, 24 clinical datasets with lesions of cerebral microbleed (CMB) and calcification, and 10 datasets with multiple sclerosis (MS).On synthetic datasets, SS-POCSnet showed the best performance among the methods evaluated, with a normalized root mean squared error of 37.3% ± 4.2%, susceptibility-tuned structured similarity index measure of 0.823 ± 0.02, high-frequency error norm of 37.0 ± 5.7, and peak signal-to-noise ratio of 42.8 ± 1.1. SS-POCSnet also reduced the underestimations of susceptibility values in deep brain nuclei compared with those from the other models evaluated. Furthermore, SS-POCSnet was sensitive to CMB/calcification and MS lesions, demonstrating its clinical applicability. Our method also supported variable imaging parameters, including matrix size and resolution. It was concluded that deep learning-regularized, single-step QSM quantification can mitigate underestimating susceptibility values in deep brain nuclei.

Prevalence of mild behavioural impairment domains: a meta-analysis.

BACKGROUND: Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterised by later life emergence of persistent neuropsychiatric symptoms. Our previous meta-analysis showed that MBI is prevalent among cognitively normal (CN), subjective cognitive impairment (SCI) and mild cognitive impairment (MCI) subjects. This study is to calculate the pooled prevalence of MBI domains among CN, SCI, and MCI subjects. METHODS: A search of relevant literature published between 1 January 2003 and 6 August 2021 was conducted. Meta-analysis using a random effects model and meta-regression was performed. RESULTS: Ten studies conducted among 12 067 subjects (9758 CN, 1057 SCI and 1252 MCI) with retrievable MBI domains data underwent meta-analysis, revealing pooled prevalence of affective dysregulation (AFD), impulse dyscontrol (IDS), decreased motivation (DMT), social inappropriateness (SIP) and abnormal perception/thought (APT) of 32.84% (95% CI 24.44-42.5%), 26.67% (95% CI 18.24-37.23%), 12.58% (95% CI 6.93-21.75%), 6.05% (95% CI 3.44-10.42%), and 2.81% (95% CI 1.67-4.69%) respectively. AFD and APT domains demonstrated ordinal increase in pooled prevalence from CN, SCI and MCI subgroups, but meta-regression demonstrated no significant difference in MBI domains prevalence among cognitive subgroups (in contrast to the significant increase in MBI prevalence from CN to SCI to MCI). The pooled prevalence of AFD and IDS are greater than that of DMT, SIP and APT among all cognitive subgroups. Several variables were found to explain the high heterogeneity. CONCLUSIONS: AFD and IDS are the two most prevalent MBI domains and remain the same with cognitive deterioration. This finding is potentially relevant to clinical practice.

Asymmetric left-right hippocampal glutamatergic modulation of cognitive control in ApoE-isoform subjects is unrelated to neuroinflammation.

The glutamatergic cycle is essential in modulating memory processing by the hippocampal circuitry. Our combined proton magnetic resonance spectroscopy (1 H-MRS) and task-based functional magnetic resonance imaging (fMRI) study (using face-name paired-associates encoding and retrieval task) of a cognitively normal cohort of 67 healthy adults (18 ApoE4 carriers and 49 non-ApoE4 carriers) found altered patterns of relationships between glutamatergic-modulated synaptic signalling and neuronal activity or functional hyperaemia in the ApoE4 isoforms. Our study highlighted the asymmetric left-right hippocampal glutamatergic system in modulating neuronal activities in ApoE4 carriers versus non-carriers. Such brain differentiation might be developmental cognitive advantages or compensatory due to impaired synaptic integrity and plasticity in ApoE4 carriers. As there was no difference in myoinositol levels measured by MRS between the ApoE4 and non-ApoE4 subgroups, the mechanism is unlikely to be a response to neuroinflammation.

A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms.

Alzheimer's disease (AD) is the commonest cause of dementia, characterized by the clinical presentation of progressive anterograde episodic memory impairment. However, atypical presentation of patients is increasingly recognized. These atypical AD include logopenic aphasia, behavioural variant AD, posterior cortical atrophy, and corticobasal syndrome. These atypical AD are more common in patients with young onset AD before the age of 65 years old. Since medical needs (including the behavioural and psychological symptoms of dementia) of atypical AD patients could be different from typical AD patients, it is important for clinicians to be aware of these atypical forms of AD. In addition, disease modifying treatment may be available in the future. This review aims at providing an update on various important subtypes of atypical AD including behavioural and psychological symptoms.

Prevalence of mild behavioural impairment: a systematic review and meta-analysis.

AIM: Mild behavioural impairment (MBI) is a neurobehavioural syndrome characterized by emergent neuropsychiatric symptoms in later life. There has been no systematic review or meta-analysis on the prevalence of MBI. The main aim of the study is to calculate the pooled prevalence of MBI. METHODS: A search of the literature on MBI in mild cognitive impairment (MCI), cognitively normal (CN), and subjective cognitive impairment (SCI) and CN but at risk (CN-AR) subjects published between 1 January 2003 and 28 September 2020 was conducted. Meta-analysis using a random effects model was performed to determine the pooled estimate of the prevalence of MBI. Meta-regression was performed to identify factors contributing to the variance of prevalence rate. A systematic review was also performed to study the impact of MBI in cognitive outcomes and its correlation to the pathology and genetics of Alzheimer's disease. RESULTS: Eleven studies conducted among 15 689 subjects underwent meta-analysis, revealing the pooled prevalence of MBI to be 33.5% (95% confidence interval (CI): 22.6%-46.6%). Seven studies conducted among 1358 MCI subjects underwent meta-analysis, revealing the pooled prevalence to be 45.5% (95%CI: 36.1%-55.3%). Four studies conducted among 13 153 CN subjects underwent meta-analysis, revealing the pooled prevalence to be 17.0% (95%CI: 7.2%-34.9%). Five studies conducted among 1158 SCI or CN-AR subjects underwent meta-analysis, revealing the pooled prevalence to be 35.8% (95%CI: 21.4%-53.2%). A systematic review of 13 studies showed that MBI has a significant impact on cognitive deterioration and is associated with the pathology and genetics of Alzheimer's disease. CONCLUSIONS: In MCI, CN, and SCI and CN-AR subjects, MBI is common. Our finding is potentially useful in planning future clinical trials.

Age-Specific Associations of Renal Impairment and Cerebral Small Vessel Disease Burden in Chinese with Ischaemic Stroke.

BACKGROUND: Recent studies in Caucasians with transient ischaemic attack or ischaemic stroke have demonstrated significant age-specific associations between cerebral small vessel disease (SVD) burden on magnetic resonance imaging and renal impairment. We aimed to validate these findings in a large cohort of Chinese with ischaemic stroke. METHODS: In 959 Chinese with ischaemic stroke who received a brain magnetic resonance imaging at the University of Hong Kong, we determined the age-specific associations of renal impairment (glomerular filtration rate < 60 mL/min/1.73 m2) with neuroimaging markers of SVD as well as with the SVD score. RESULTS: Although renal impairment was associated with the SVD score in univariate analysis in all patients (odds ratio 1.61, 95% confidence interval 1.24-2.09, P < .0001), these associations were attenuated after adjusting for age and sex (P = .38). Similar findings were noted in patients with ischaemic stroke due to SVD and non-SVD subtypes. However, in 222 of 959 patients aged <60, renal impairment was independently associated with an increasing microbleed (adjusted odds ratio 6.82, 2.26-20.59), subcortical (4.97, 1.62-15.24) periventricular white matter hyperintensity (3.96, 1.08-14.51) and global SVD burden (3.41, 1.16-10.04; all P < .05) even after adjusting for age, sex, and vascular risk factors. Nevertheless, there were no associations between renal impairment and individual neuroimaging markers of SVD nor with the SVD score in patients aged ≥60 after adjusting for age and sex (all P > .05). CONCLUSIONS: In Chinese with ischaemic stroke, renal impairment was independently associated with microbleed, white matter hyperintensity and global SVD burden in individuals aged <60, but not in those aged ≥60, suggesting that there may be shared susceptibilities to premature systemic disease.

Antiplatelet Treatment After Transient Ischemic Attack and Ischemic Stroke in Patients With Cerebral Microbleeds in 2 Large Cohorts and an Updated Systematic Review.

BACKGROUND AND PURPOSE: In patients with transient ischemic attack/ischemic stroke, microbleed burden predicts intracerebral hemorrhage (ICH), and ischemic stroke, but implications for antiplatelet treatment are uncertain. Previous cohort studies have had insufficient follow-up to assess the time course of risks, have not stratified risks by antithrombotic use, and have not reported extracranial bleeds or functional outcome of ICH versus ischemic stroke. METHODS: In 2 independent prospective cohorts with transient ischemic attack/ischemic stroke (Oxford Vascular Study/mainly white; University of Hong Kong/mainly Chinese), antiplatelet treatment was started routinely irrespective of microbleed burden. Risks, time course and outcome of ICH, extracranial bleeds, and recurrent ischemic events were determined and stratified by microbleed burden (0 versus 1, 2-4, and ≥5), adjusting for age, sex, and vascular risk factors. RESULTS: Microbleeds were more frequent in the Chinese cohort (450 of 1003 versus 165 of 1080; P<0.0001), but risk associations were similar during 7433 patient-years of follow-up. Among 1811 patients on antiplatelet drugs, risk of major extracranial bleeds was unrelated to microbleed burden (Ptrend=0.87), but the 5-year risk of ICH was steeply related (Ptrend<0.0001), with 11 of 15 (73%) of ICH in 140 of 1811 (7.7%) patients with ≥5 microbleeds. However, risk of ischemic stroke also increased with microbleed burden (Ptrend=0.013), such that risk of ischemic stroke and coronary events exceeded ICH and major extracranial bleeds during the first year, even among patients with ≥5 microbleeds (11.6% versus 3.9%). However, this ratio changed over time, with risk of hemorrhage (11.2%) matching that of ischemic events (12.0%) after 1 year. Moreover, whereas the association between microbleed burden and risk of ischemic stroke was due mainly to nondisabling events (Ptrend=0.007), the association with ICH was accounted for (Ptrend<0.0001) by disabling/fatal events (≥5 microbleeds: 82% disabling/fatal ICH versus 40% disabling/fatal ischemic stroke; P=0.035). CONCLUSIONS: In white and Chinese patients with ≥5 microbleeds, withholding antiplatelet drugs during the first year after transient ischemic attack/ischemic stroke may be inappropriate. However, the risk of ICH may outweigh any benefit thereafter.

Differential brainstem atrophy patterns in multiple sclerosis and neuromyelitis optica spectrum disorders.

BACKGROUND: Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) inflammatory demyelinating disorders. It is clinically important to distinguish MS from NMOSD, as treatment and prognosis differ. Brainstem involvement is common in both disorders. PURPOSE: To investigate whether the patterns of brainstem atrophy on volumetric analysis in MS and NMOSD were different and correlated with clinical disability. STUDY TYPE: Case-control cross-sectional study. SUBJECTS: In all, 17 MS, 13 NMOSD, and 18 healthy control (HC) subjects were studied. FIELD STRENGTH/SEQUENCE: T1 -weighted and T2 w spin-echo images were acquired with a 3T scanner. ASSESSMENT: Semiautomated segmentation and volumetric measurement of brainstem regions were performed. Anatomical information was obtained from whole brain T1 w images using a 3D magnetization-prepared rapid gradient-echo (MPRAGE) imaging sequence (TR/TE/T: 7.0/3.2/800 msec, voxel size: 1 × 1 × 1 mm3 , scan time: 10 min 41 sec). STATISTICAL TESTS: Independent samples t-test, Mann-Whitney U-test, partial correlation, and multiple regression analysis. RESULTS: Baseline characteristics were similar across the three groups, without significant difference in disease duration (P = 0.354) and EDSS score (P = 0.159) between MS and NMOSD subjects. Compared to HC, MS subjects had significantly smaller normalized whole brainstem (-5.2%, P = 0.027), midbrain (-8.3%, P = 0.0001), and pons volumes (-5.9%, P = 0.048), while only the normalized medulla volume was significantly smaller in NMOSD subjects compared to HC (-8.5% vs. HC, P = 0.024). Normalized midbrain volume was significantly smaller in MS compared to NMOSD subjects (-5.0%, P = 0.014), whereas normalized medulla volume was significantly smaller in NMOSD compared to MS subjects (-8.1%, P = 0.032). Partial correlations and multiple regression analysis revealed that smaller normalized whole brainstem, pons, and medulla oblongata volumes were associated with greater disability on the Expanded Disability Status Scale (EDSS), Functional System Score (FSS)-brainstem and FSS-cerebellar in NMOSD subjects. DATA CONCLUSION: Differential patterns of brainstem atrophy were observed, with the midbrain being most severely affected followed by pons in MS, whereas only the medulla oblongata was affected in NMOSD. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1601-1609.

Clinical Correlates, Ethnic Differences, and Prognostic Implications of Perivascular Spaces in Transient Ischemic Attack and Ischemic Stroke.

BACKGROUND AND PURPOSE: Perivascular spaces (PVSs) are considered markers of small vessel disease. However, their long-term prognostic implications in transient ischemic attack/ischemic stroke patients are unknown. Ethnic differences in PVS prevalence are also unknown. METHODS: Two independent prospective studies were conducted, 1 comprising predominantly whites with transient ischemic attack/ischemic stroke (OXVASC [Oxford Vascular] study) and 1 comprising predominantly Chinese with ischemic stroke (University of Hong Kong). Clinical and imaging correlates, prognostic implications for stroke and death, and ethnic differences in basal ganglia (BG) and centrum semiovale (CS) PVSs were studied with adjustment for age, sex, vascular risk factors, and scanner strength. RESULTS: Whites with transient ischemic attack/ischemic stroke (n=1028) had a higher prevalence of both BG and CS-PVSs compared with Chinese (n=974; >20 BG-PVSs: 22.4% versus 7.1%; >20 CS-PVSs: 45.8% versus 10.4%; P<0.0001). More than 20 BG or CS-PVSs were both associated with increasing age and white matter hyperintensity, although associations with BG-PVSs were stronger (all P<0.0001). During 6924 patient-years of follow-up, BG-PVSs were also independently associated with an increased risk of recurrent ischemic stroke (adjusted hazard ratio compared with <11 PVSs, 11-20 PVSs: HR, 1.15; 95% confidence interval, 0.78-1.68; >20 PVSs: HR, 1.82; 1.18-2.80; P=0.011) but not intracerebral hemorrhage (P=0.10) or all-cause mortality (P=0.16). CS-PVSs were not associated with recurrent stroke (P=0.57) or mortality (P=0.072). Prognostic associations were similar in both cohorts. CONCLUSIONS: Over and above ethnic differences in frequency of PVSs in transient ischemic attack/ischemic stroke patients, BG and CS-PVSs had similar risk factors, but although >20 BG-PVSs were associated with an increased risk of recurrent ischemic stroke, CS-PVSs were not.

Application of diffusional kurtosis imaging to detect occult brain damage in multiple sclerosis and neuromyelitis optica.

Multiple sclerosis (MS) and neuromyelitis optica (NMO) are two common types of inflammatory demyelinating disease of the central nervous system. Early distinction of NMO from MS is crucial but quite challenging. In this study, 13 NMO spectrum disorder patients (Expanded Disability Status Scale (EDSS) of 3.0 ± 1.7, ranging from 2 to 6.5; disease duration of 5.3 ± 4.7 years), 17 relapsing-remitting MS patients (EDSS of 2.6 ± 1.4, ranging from 1 to 5.5; disease duration of 7.9 ± 7.8 years) and 18 healthy volunteers were recruited. Diffusional kurtosis imaging was employed to discriminate NMO and MS patients at the early or stable stage from each other, and from healthy volunteers. The presence of alterations in diffusion and diffusional kurtosis metrics in normal-appearing white matter (NAWM) and diffusely increased mean diffusivity (MD) in the cortical normal-appearing gray matter (NAGM) favors the diagnosis of MS rather than NMO. Meanwhile, normal diffusivities and kurtosis metrics in all NAWM as well as increases in MD in the frontal and temporal NAGM suggest NMO. Our results suggest that diffusion and diffusional kurtosis metrics may well aid in discriminating the two diseases.

Effective time window in reducing pituitary adenoma size by gamma knife radiosurgery.

OBJECTIVES: Although the effectiveness of gamma knife radiosurgery (GKRS) in controlling the size of pituitary adenomas has been well demonstrated in many studies, the time period in which significant changes in tumor size occurs has been investigated in a limited fashion. It is important to determine the therapeutic window of GKRS in treating pituitary adenomas, i.e., the effective timeframe during which significant size reduction of these tumors occurs, so that alternative treatments such as further GKRS or microsurgery might be prescribed in a timely manner if clinically indicated. METHODS: This was a nested sample of an ongoing local cohort study on GKRS for pituitary adenomas at the University of Virginia. Magnetic resonance imaging (MRI) using dedicated sequences was employed. Only patients with a baseline MRI (TP0) and at least 1 follow-up study performed in the University Hospital after GKRS were included. The follow-up scans were performed at five time-points (TP1-TP5) which were 6, 12, 24, 36 and 48 months after GKRS. The dimensional indices of the tumors were measured in three orthogonal planes, i.e., transverse (TR), antero-posterior (AP) and cranio-caudal (CC). The volumes of the tumors were estimated by using the following formula: [Formula: see text]. Tumor volume decrease by more than 25% from baseline was considered as 'shrinkage', <25% tumor size increase or decrease was considered 'static', and more than 25% increase as 'increment'. Our cohort consisted of 21 patients, with functioning adenomas in 13 subjects i.e. six adrenocorticotrophic hormone (ACTH)-secreting and seven growth hormone (GH)-secreting, and non-functioning (NF) adenomas in eight subjects. RESULTS: In 26 adenomas (8 ACTH, 9 GH and 9 NF), tumor control (tumor shrinkage or static) were achieved in 21 tumors (80.8%); 89, 75, and 78% for GH-secreting, ACTH-secreting and NF adenomas respectively, at the end of the 4-year follow-up period. Analysis of variance showed significant differences of GKRS margin dose among different types of tumors (p = 0.013), but not of baseline tumor volumes (p = 0.240). Logistic regression analysis showed no significant association of margin dose, baseline volume or tumor type with the tumor control outcome. Comparison of tumor change using dimensional indices relative to the base time point (TP0) showed that in the sample there was an average reduction of 1.290 mm at TP1 (6 months) with p values 0.155 (parametric t test) and 0.098 (non-parametric Wilcoxon signed-ranked test) respectively, showing a moderate reduction in tumor dimensional indices. The change in dimensional indices at later time points (TP2-TP5) showed an average reduction ranging from 1.930 to 2.471 mm. Significant reduction in the mean dimensional indices was firstly observed at TP2 (1 year) with p values 0.013 (t test) and 0.018 (Wilcoxon signed-rank test). Such scale of reduction in the dimensional indices appeared to be maintained along the time axis (from TP2 to TP5). CONCLUSIONS: Significant decrease in tumor dimensional indices tended to occur at 1 year post-GKRS. Although to a lesser extent, such decrease in dimensional indices continued up to the end of our follow-up period.

Dynamic Changes in Long-Standing Multiple Sclerosis Revealed by Longitudinal Structural Network Analysis Using Diffusion Tensor Imaging.

BACKGROUND AND PURPOSE: DTI can be used to derive conventional diffusion measurements, which can measure WM abnormalities in multiple sclerosis. DTI can also be used to construct structural brain networks and derive network measurements. However, few studies have compared their sensitivity in detecting brain alterations, especially in longitudinal studies. Therefore, in this study, we aimed to determine which type of measurement is more sensitive in tracking the dynamic changes over time in MS. MATERIALS AND METHODS: Eighteen patients with MS were recruited at baseline and followed up at 6 and 12 months. All patients underwent MR imaging and clinical evaluation at 3 time points. Diffusion and network measurements were derived, and their brain changes were evaluated. RESULTS: None of the conventional DTI measurements displayed statistically significant changes during the follow-up period; however, the nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part showed significant longitudinal changes between baseline and at 12 months, respectively. CONCLUSIONS: The nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part may be used to monitor brain changes over time in MS.

Disrupted Structural White Matter Network in Alzheimer's Disease Continuum, Vascular Dementia, and Mixed Dementia: A Diffusion Tensor Imaging Study.

BACKGROUND: Dementia presents a significant burden to patients and healthcare systems worldwide. Early and accurate diagnosis, as well as differential diagnosis of various types of dementia, are crucial for timely intervention and management. However, there is currently a lack of clinical tools for accurately distinguishing between these types. OBJECTIVE: This study aimed to investigate the differences in the structural white matter (WM) network among different types of cognitive impairment/dementia using diffusion tensor imaging, and to explore the clinical relevance of the structural network. METHODS: A total of 21 normal control, 13 subjective cognitive decline (SCD), 40 mild cognitive impairment (MCI), 22 Alzheimer's disease (AD), 13 mixed dementia (MixD), and 17 vascular dementia (VaD) participants were recruited. Graph theory was utilized to construct the brain network. RESULTS: Our findings revealed a monotonic trend of disruption in the brain WM network (VaD > MixD > AD > MCI > SCD) in terms of decreased global efficiency, local efficiency, and average clustering coefficient, as well as increased characteristic path length. These network measurements were significantly associated with the clinical cognition index in each disease group separately. CONCLUSION: These findings suggest that structural WM network measurements can be utilized to differentiate between different types of cognitive impairment/dementia, and these measurements can provide valuable cognition-related information.

The Use of Diffusion Kurtosis Imaging for the Differential Diagnosis of Alzheimer's Disease Spectrum.

Structural and diffusion kurtosis imaging (DKI) can be used to assess hippocampal macrostructural and microstructural alterations respectively, in Alzheimer's disease (AD) spectrum, spanning from subjective cognitive decline (SCD) to mild cognitive impairment (MCI) and AD. In this study, we explored the diagnostic performance of structural imaging and DKI of the hippocampus in the AD spectrum. Eleven SCD, thirty-seven MCI, sixteen AD, and nineteen age- and sex-matched normal controls (NCs) were included. Bilateral hippocampal volume, mean diffusivity (MD), and mean kurtosis (MK) were obtained. We detected that in AD vs. NCs, the right hippocampal volume showed the most prominent AUC value (AUC = 0.977); in MCI vs. NCs, the right hippocampal MD was the most sensitive discriminator (AUC = 0.819); in SCD vs. NCs, the left hippocampal MK was the most sensitive biomarker (AUC = 0.775). These findings suggest that, in the predementia stage (SCD and MCI), hippocampal microstructural changes are predominant, and the best discriminators are microstructural measurements (left hippocampal MK for SCD and right hippocampal MD for MCI); while in the dementia stage (AD), hippocampal macrostructural alterations are superior, and the best indicator is the macrostructural index (right hippocampal volume).

Cuprizone drives divergent neuropathological changes in different mouse models of Alzheimer's disease.

Myelin degradation is a normal feature of brain aging that accelerates in Alzheimer's disease (AD). To date, however, the underlying biological basis of this correlation remains elusive. The amyloid cascade hypothesis predicts that demyelination is caused by increased levels of the ß-amyloid (Aß) peptide. Here we report on work supporting the alternative hypothesis that early demyelination is upstream of amyloid. We challenged two different mouse models of AD (R1.40 and APP/PS1) using cuprizone-induced demyelination and tracked the responses with both neuroimaging and neuropathology. In oppose to amyloid cascade hypothesis, R1.40 mice, carrying only a single human mutant APP (Swedish; APP SWE ) transgene, showed a more abnormal changes of magnetization transfer ratio and diffusivity than in APP/PS1 mice, which carry both APP SWE and a second PSEN1 transgene (delta exon 9; PSEN1 dE9 ). Although cuprizone targets oligodendrocytes (OL), magnetic resonance spectroscopy and targeted RNA-seq data in R1.40 mice suggested a possible metabolic alternation in axons. In support of alternative hypotheses, cuprizone induced significant intraneuronal amyloid deposition in young APP/PS1, but not in R1.40 mice, and it suggested the presence of PSEN deficiencies, may accelerate Aß deposition upon demyelination. In APP/PS1, mature OL is highly vulnerable to cuprizone with significant DNA double strand breaks (53BP1 + ) formation. Despite these major changes in myelin, OLs, and Aß immunoreactivity, no cognitive impairment or hippocampal pathology was detected in APP/PS1 mice after cuprizone treatment. Together, our data supports the hypothesis that myelin loss can be the cause, but not the consequence, of AD pathology. SIGNIFICANCE STATEMENT: The causal relationship between early myelin loss and the progression of Alzheimer's disease remains unclear. Using two different AD mouse models, R1.40 and APP/PS1, our study supports the hypothesis that myelin abnormalities are upstream of amyloid production and deposition. We find that acute demyelination initiates intraneuronal amyloid deposition in the frontal cortex. Further, the loss of oligodendrocytes, coupled with the accelerated intraneuronal amyloid deposition, interferes with myelin tract diffusivity at a stage before any hippocampus pathology or cognitive impairments occur. We propose that myelin loss could be the cause, not the consequence, of amyloid pathology during the early stages of Alzheimer's disease.

A Pilot Study of Short-Course Oral Vitamin A and Aerosolised Diffuser Olfactory Training for the Treatment of Smell Loss in Long COVID.

Background: Olfactory dysfunction (OD) is a common neurosensory manifestation in long COVID. An effective and safe treatment against COVID-19-related OD is needed. Methods: This pilot trial recruited long COVID patients with persistent OD. Participants were randomly assigned to receive short-course (14 days) oral vitamin A (VitA; 25,000 IU per day) and aerosolised diffuser olfactory training (OT) thrice daily (combination), OT alone (standard care), or observation (control) for 4 weeks. The primary outcome was differences in olfactory function by butanol threshold tests (BTT) between baseline and end-of-treatment. Secondary outcomes included smell identification tests (SIT), structural MRI brain, and serial seed-based functional connectivity (FC) analyses in the olfactory cortical network by resting-state functional MRI (rs-fMRI). Results: A total of 24 participants were randomly assigned to receive either combination treatment (n = 10), standard care (n = 9), or control (n = 5). Median OD duration was 157 days (IQR 127-175). Mean baseline BTT score was 2.3 (SD 1.1). At end-of-treatment, mean BTT scores were significantly higher for the combination group than control (p < 0.001, MD = 4.4, 95% CI 1.7 to 7.2) and standard care (p = 0.009) groups. Interval SIT scores increased significantly (p = 0.009) in the combination group. rs-fMRI showed significantly higher FC in the combination group when compared to other groups. At end-of-treatment, positive correlations were found in the increased FC at left inferior frontal gyrus and clinically significant improvements in measured BTT (r = 0.858, p < 0.001) and SIT (r = 0.548, p = 0.042) scores for the combination group. Conclusions: Short-course oral VitA and aerosolised diffuser OT was effective as a combination treatment for persistent OD in long COVID.

Changes in the Intranetwork and Internetwork Connectivity of the Default Mode Network and Olfactory Network in Patients with COVID-19 and Olfactory Dysfunction.

Olfactory dysfunction (OD) is a common symptom in coronavirus disease 2019 (COVID-19) patients. Moreover, many neurological manifestations have been reported in these patients, suggesting central nervous system involvement. The default mode network (DMN) is closely associated with olfactory processing. In this study, we investigated the internetwork and intranetwork connectivity of the DMN and the olfactory network (ON) in 13 healthy controls and 22 patients presenting with COVID-19-related OD using independent component analysis and region of interest functional magnetic resonance imaging (fMRI) analysis. There was a significant correlation between the butanol threshold test (BTT) and the intranetwork connectivity in ON. Meanwhile, the COVID-19 patients with OD showed significantly higher intranetwork connectivity in the DMN, as well as higher internetwork connectivity between ON and DMN. However, no significant difference was found between groups in the intranetwork connectivity within ON. We postulate that higher intranetwork functional connectivities compensate for the deficits in olfactory processing and general well-being in COVID-19 patients. Nevertheless, the compensation process in the ON may not be obvious at this stage. Our results suggest that resting-state fMRI is a potentially valuable tool to evaluate neurosensory dysfunction in COVID-19 patients.

Incremental diagnostic value of 18F-Fluetemetamol PET in differential diagnoses of Alzheimer's Disease-related neurodegenerative diseases from an unselected memory clinic cohort.

To evaluate the incremental diagnostic value of 18F-Flutemetamol PET following MRI measurements on an unselected prospective cohort collected from a memory clinic. A total of 84 participants was included in this study. A stepwise study design was performed including initial analysis (based on clinical assessments), interim analysis (revision of initial analysis post-MRI) and final analysis (revision of interim analysis post-18F-Flutemetamol PET). At each time of evaluation, every participant was categorized into SCD, MCI or dementia syndromal group and further into AD-related, non-AD related or non-specific type etiological subgroup. Post 18F-Flutemetamol PET, the significant changes were seen in the syndromal MCI group (57%, p < 0.001) involving the following etiological subgroups: AD-related MCI (57%, p < 0.01) and non-specific MCI (100%, p < 0.0001); and syndromal dementia group (61%, p < 0.0001) consisting of non-specific dementia subgroup (100%, p < 0.0001). In the binary regression model, amyloid status significantly influenced the diagnostic results of interim analysis (p < 0.01). 18F-Flutemetamol PET can have incremental value following MRI measurements, particularly reflected in the change of diagnosis of individuals with unclear etiology and AD-related-suspected patients due to the role in complementing AD-related pathological information.

A data-driven deep learning pipeline for quantitative susceptibility mapping (QSM).

PURPOSE: This study developed a data-driven optimization to improve the accuracy of deep learning QSM quantification. METHODS: The proposed deep learning QSM pipeline consisted of two projections onto convex set (POCS) models designed to decouple trainable network components with the spherical mean value (SMV) filters and dipole kernel in the data-driven optimization. They were a background field removal network (named POCSnet1) and a dipole inversion network (named POCSnet2). Both POCSnet1 and POCSnet2 were the unrolled V-Net with iterative data-driven optimization to enforce the data fidelity. For training POCSnet1, we simulated phantom data with random geometric shapes as the background susceptibility sources. For training POCSnet2, we used geometric shapes to mimic the QSM. The evaluation was performed on synthetic data, a public COSMOS (N = 1), and clinical data from a Parkinson's disease cohort (N = 71) and small-vessel disease cohort (N = 26). For comparison, DLL2, FINE, and autoQSM, were implemented and tested under the same experimental setting. RESULTS: On COSMOS, results from POCSnet1 were more similar to that of the V-SHARP method with NRMSE = 23.7% and SSIM = 0.995, compared with the NRMSE = 62.7% and SSIM = 0.975 for SHARQnet, a naïve V-Net model. On COSMOS, the NRMSE and HFEN for POCSnet2 were 58.1% and 56.7%; while for DLL2, FINE, and autoQSM, they were 62.0% and 61.2%, 69.8% and 67.5%, and 87.5% and 85.3%, respectively. On the Parkinson's disease cohort, our results were consistent with those obtained from VSHARP+STAR-QSM with biases <3% and outperformed the SHARQnet+DeepQSM that had biases of 7% to 10%. The sensitivity of cerebral microbleed detection using our pipeline was 100%, compared with 92% by SHARQnet+DeepQSM. CONCLUSION: Data-driven optimization improved the accuracy of QSM quantification compared with that of naïve V-Net models.

Associations of sleep apnea risk and oxygen desaturation indices with cerebral small vessel disease burden in patients with stroke.

Background: Obstructive sleep apnea (OSA) is associated with cerebral small vessel disease (CSVD). Nonetheless, whether OSA-risk determined by a simple screening questionnaire or indices quantifying nocturnal hypoxemia other than the conventional apnea-hypopnea index (AHI) by the home sleep apnea test (HSAT) associated with CSVD burden remains uncertain. Methods: From 2018 to 2021, we recruited patients with transient ischemic attack (TIA)/minor stroke from the Queen Mary Hospital Acute Stroke Unit and TIA/Stroke Outpatient Clinics. Logistic regression models were applied to determine the association of baseline OSA-risk (on STOP-BANG questionnaire) or HSAT-derived indices quantifying nocturnal hypoxemia with global burden/individual markers of CSVD on MRI. Indices included oxygen desaturation (≥3%) index (ODI), minimum oxygen saturation (SpO2), percentage of total sleep time with an oxygen saturation <90% (CT90%), and desaturation duration (≥3%, DesDur). Results: In 283 patients with TIA/minor stroke (mean age 65 years, 64% men), OSA-risk was significantly associated with total CSVD score (multivariate-adjusted odds ratio: 1.23, 95% confidence interval 1.01-1.51), presence of lacunes [1.39 (1.09-1.79)] and burden of basal ganglia PVSs [1.32 (1.06-1.67)]. In 85/283 patients who completed HSAT, neither AHI, minimum SpO2 nor CT90% was associated with CSVD burden. Nonetheless, ODI and DesDur remained significantly associated with total CSVD score after covariate adjustment: ODI [1.04 (1.01-1.07)] and DesDur [1.04 (1.01-1.08)]. Conclusion: In patients with TIA/minor stroke, high OSA-risk was associated with a greater CSVD burden. Oxygen desaturation indices (ODI and DesDur) rather than AHI were independently associated with global CSVD burden, indicating that longer and more severe desaturations may contribute to the pathogenesis of CSVD.