Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Distinct spatial contributions of amyloid pathology and cerebral small vessel disease to hippocampal morphology.

INTRODUCTION: Cerebral small vessel disease (SVD) and amyloid beta (Aß) pathology frequently co-exist. The impact of concurrent pathology on the pattern of hippocampal atrophy, a key substrate of memory impacted early and extensively in dementia, remains poorly understood. METHODS: In a unique cohort of mixed Alzheimer's disease and moderate-severe SVD, we examined whether total and regional neuroimaging measures of SVD, white matter hyperintensities (WMH), and Aß, as assessed by 18F-AV45 positron emission tomography, exert additive or synergistic effects on hippocampal volume and shape. RESULTS: Frontal WMH, occipital WMH, and Aß were independently associated with smaller hippocampal volume. Frontal WMH had a spatially distinct impact on hippocampal shape relative to Aß. In contrast, hippocampal shape alterations associated with occipital WMH spatially overlapped with Aß-vulnerable subregions. DISCUSSION: Hippocampal degeneration is differentially sensitive to SVD and Aß pathology. The pattern of hippocampal atrophy could serve as a disease-specific biomarker, and thus guide clinical diagnosis and individualized treatment strategies for mixed dementia.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Predictors of multiple sclerosis progression: A systematic review of conventional magnetic resonance imaging studies.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic neurodegenerative disorder that affects the central nervous system (CNS) and results in progressive clinical disability and cognitive decline. Currently, there are no specific imaging parameters available for the prediction of longitudinal disability in MS patients. Magnetic resonance imaging (MRI) has linked imaging anomalies to clinical and cognitive deficits in MS. In this study, we aimed to evaluate the effectiveness of MRI in predicting disability, clinical progression, and cognitive decline in MS. METHODS: In this study, according to PRISMA guidelines, we comprehensively searched the Web of Science, PubMed, and Embase databases to identify pertinent articles that employed conventional MRI in the context of Relapsing-Remitting and progressive forms of MS. Following a rigorous screening process, studies that met the predefined inclusion criteria were selected for data extraction and evaluated for potential sources of bias. RESULTS: A total of 3028 records were retrieved from database searching. After a rigorous screening, 53 records met the criteria and were included in this study. Lesions and alterations in CNS structures like white matter, gray matter, corpus callosum, thalamus, and spinal cord, may be used to anticipate disability progression. Several prognostic factors associated with the progression of MS, including presence of cortical lesions, changes in gray matter volume, whole brain atrophy, the corpus callosum index, alterations in thalamic volume, and lesions or alterations in cross-sectional area of the spinal cord. For cognitive impairment in MS patients, reliable predictors include cortical gray matter volume, brain atrophy, lesion characteristics (T2-lesion load, temporal, frontal, and cerebellar lesions), white matter lesion volume, thalamic volume, and corpus callosum density. CONCLUSION: This study indicates that MRI can be used to predict the cognitive decline, disability progression, and disease progression in MS patients over time.

Impact of amyloid and tau positivity on longitudinal brain atrophy in cognitively normal individuals.

BACKGROUND: Individuals on the preclinical Alzheimer's continuum, particularly those with both amyloid and tau positivity (A + T +), display a rapid cognitive decline and elevated disease progression risk. However, limited studies exist on brain atrophy trajectories within this continuum over extended periods. METHODS: This study involved 367 ADNI participants grouped based on combinations of amyloid and tau statuses determined through cerebrospinal fluid tests. Using longitudinal MRI scans, brain atrophy was determined according to the whole brain, lateral ventricle, and hippocampal volumes and cortical thickness in AD-signature regions. Cognitive performance was evaluated with the Preclinical Alzheimer's Cognitive Composite (PACC). A generalized linear mixed-effects model was used to examine group × time interactions for these measures. In addition, progression risks to mild cognitive impairment (MCI) or dementia were compared among the groups using Cox proportional hazards models. RESULTS: A total of 367 participants (48 A + T + , 86 A + T - , 63 A - T + , and 170 A - T - ; mean age 73.8 years, mean follow-up 5.1 years, and 47.4% men) were included. For the lateral ventricle and PACC score, the A + T - and A + T + groups demonstrated statistically significantly greater volume expansion and cognitive decline over time than the A - T - group (lateral ventricle: ß = 0.757 cm3/year [95% confidence interval 0.463 to 1.050], P < .001 for A + T - , and ß = 0.889 cm3/year [0.523 to 1.255], P < .001 for A + T + ; PACC: ß = - 0.19 /year [- 0.36 to - 0.02], P = .029 for A + T - , and ß = - 0.59 /year [- 0.80 to - 0.37], P < .001 for A + T +). Notably, the A + T + group exhibited additional brain atrophy including the whole brain (ß = - 2.782 cm3/year [- 4.060 to - 1.504], P < .001), hippocampus (ß = - 0.057 cm3/year [- 0.085 to - 0.029], P < .001), and AD-signature regions (ß = - 0.02 mm/year [- 0.03 to - 0.01], P < .001). Cox proportional hazards models suggested an increased risk of progressing to MCI or dementia in the A + T + group versus the A - T - group (adjusted hazard ratio = 3.35 [1.76 to 6.39]). CONCLUSIONS: In cognitively normal individuals, A + T + compounds brain atrophy and cognitive deterioration, amplifying the likelihood of disease progression. Therapeutic interventions targeting A + T + individuals could be pivotal in curbing brain atrophy, cognitive decline, and disease progression.

External evaluation of a deep learning-based approach for automated brain volumetry in patients with huntington's disease.

A crucial step in the clinical adaptation of an AI-based tool is an external, independent validation. The aim of this study was to investigate brain atrophy in patients with confirmed, progressed Huntington's disease using a certified software for automated volumetry and to compare the results with the manual measurement methods used in clinical practice as well as volume calculations of the caudate nuclei based on manual segmentations. Twenty-two patients were included retrospectively, consisting of eleven patients with Huntington's disease and caudate nucleus atrophy and an age- and sex-matched control group. To quantify caudate head atrophy, the frontal horn width to intercaudate distance ratio and the intercaudate distance to inner table width ratio were obtained. The software mdbrain was used for automated volumetry. Manually measured ratios and automatically measured volumes of the groups were compared using two-sample t-tests. Pearson correlation analyses were performed. The relative difference between automatically and manually determined volumes of the caudate nuclei was calculated. Both ratios were significantly different between the groups. The automatically and manually determined volumes of the caudate nuclei showed a high level of agreement with a mean relative discrepancy of - 2.3 ± 5.5%. The Huntington's disease group showed significantly lower volumes in a variety of supratentorial brain structures. The highest degree of atrophy was shown for the caudate nucleus, putamen, and pallidum (all p < .0001). The caudate nucleus volume and the ratios were found to be strongly correlated in both groups. In conclusion, in patients with progressed Huntington's disease, it was shown that the automatically determined caudate nucleus volume correlates strongly with measured ratios commonly used in clinical practice. Both methods allowed clear differentiation between groups in this collective. The software additionally allows radiologists to more objectively assess the involvement of a variety of brain structures that are less accessible to standard semiquantitative methods.

Regional MRI volumetry using NeuroQuant versus visual rating scales in patients with cognitive impairment and dementia.

BACKGROUND AND PURPOSE: The aims were to compare the novel regional brain volumetric measures derived by the automatic software NeuroQuant (NQ) with clinically used visual rating scales of medial temporal lobe atrophy (MTA), global cortical atrophy-frontal (GCA-f), and posterior atrophy (PA) brain regions, assessing their diagnostic validity, and to explore if combining automatic and visual methods would increase diagnostic prediction accuracy. METHODS: Brain magnetic resonance imaging (MRI) examinations from 86 patients with subjective and mild cognitive impairment (i.e., non-dementia, n = 41) and dementia (n = 45) from the Memory Clinic at Oslo University Hospital were assessed using NQ volumetry and with visual rating scales. Correlations, receiver operating characteristic analyses calculating area under the curves (AUCs) for diagnostic accuracy, and logistic regression analyses were performed. RESULTS: The correlations between NQ volumetrics and visual ratings of corresponding regions were generally high between NQ hippocampi/temporal volumes and MTA (r = -0.72/-0.65) and between NQ frontal volume and GCA-f (r = -0.62) but lower between NQ parietal/occipital volumes and PA (r = -0.49/-0.37). AUCs of each region, separating non-dementia from dementia, were generally comparable between the two methods, except that NQ hippocampi volume did substantially better than visual MTA (AUC = 0.80 vs. 0.69). Combining both MRI methods increased only the explained variance of the diagnostic prediction substantially regarding the posterior brain region. CONCLUSIONS: The findings of this study encourage the use of regional automatic volumetry in locations lacking neuroradiologists with experience in the rating of atrophy typical of neurodegenerative diseases, and in primary care settings.

Utility of visual rating scales in primary progressive aphasia.

INTRODUCTION: Differential diagnosis among subjects with Primary Progressive Aphasia (PPA) can be challenging. Structural MRI can support the clinical profile. Visual rating scales are a simple and reliable tool to assess brain atrophy in the clinical setting. The aims of the study were to establish to what extent the visual rating scales could be useful in the differential diagnosis of PPA, to compare the clinical diagnostic impressions derived from routine MRI interpretations with those obtained using the visual rating scale and to correlate results of the scales in a voxel-based morphometry (VBM) analysis. METHOD: Patients diagnosed with primary progressive aphasia (PPA) according to current criteria from two centers-Ospedale Maggiore Policlinico of Milan and Hospital Clínic de Barcelona-were included in the study. Two blinded clinicians evaluated the subjects MRIs for cortical atrophy and white matter hyperintensities using two protocols: routine readings and the visual rating scale. The diagnostic accuracy between patients and controls and within PPA subgroups were compared between the two protocols. RESULTS: One hundred fifty Subjects were studied. All the scales showed a good to excellent intra and inter-rater agreement. The left anterior temporal scale could differentiate between semantic PPA and all other variants. The rater impression after the protocol can increase the accuracy just for the logopenic PPA. In the VBM analysis, the scores of visual rating scales correlate with the corresponding area of brain atrophy. CONCLUSION: The Left anterior temporal rating scale can distinguish semantic PPA from other variants. The rater impression after structured view improved the diagnostic accuracy of logopenic PPA compared to normal readings. The unstructured view of the MRI was reliable for identifying semantic PPA and controls. Neither the structured nor the unstructured view could identify the nonfluent and undetermined variants.

Clinical predictors of Alzheimer's disease-like brain atrophy in individuals with memory complaints.

OBJECTIVES: The definition and assessment methods for subjective cognitive decline (SCD) vary among studies. We aimed to investigate which features or assessment methods of SCD best predict Alzheimer's disease (AD)-related structural atrophy patterns. METHODS: We assessed 104 individuals aged 55+ with memory complaints but normal cognitive screening. Our research questions were as follows: To improve the prediction of AD related morphological changes, (1) Would the use of a standardized cognitive screening scale be beneficial? (2) Is conducting a thorough neuropsychological evaluation necessary instead of relying solely on cognitive screening tests? (3) Should we apply SCD-plus research criteria, and if so, which criterion would be the most effective? (4) Is it necessary to consider medical and psychiatric comorbidities, vitamin deficiencies, vascular burden on MRI, and family history? We utilized Freesurfer to analyze cortical thickness and regional brain volume meta-scores linked to AD or predicting its development. We employed multiple linear regression models for each variable, with morphology as the dependent variable. RESULTS: AD-like morphology was associated with subjective complaints in males, individuals with advanced age, and higher education. Later age of onset for complaints, complaints specifically related to memory, excessive deep white matter vascular lesions, and using medications that have negative implications for cognitive health (according to the Beers criteria) were predictive of AD-related morphology. The subjective cognitive memory questionnaire scores were found to be a better predictor of reduced volumes than a single-question assessment. It is important to note that not all SCD-plus criteria were evaluated in this study, particularly the APOE genotype, amyloid, and tau status, due to resource limitations. CONCLUSIONS: The detection of AD-related structural changes is impacted by demographics and assessment methods. Standardizing SCD assessment methods can enhance predictive accuracy.

Alzheimer's and neurodegenerative disease biomarkers in blood predict brain atrophy and cognitive decline.

BACKGROUND: Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer's disease (AD) pathology (amyloid-ß [Aß42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-ß status modified these associations. METHODS: Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. RESULTS: Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aß42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aß42/40 (higher Aß burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aß burden, as was the association of higher GFAP with memory decline. CONCLUSIONS: Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

Vulnerability of Thalamic Nuclei at CSF Interface During the Entire Course of Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Thalamic atrophy can be used as a proxy for neurodegeneration in multiple sclerosis (MS). Some data point toward thalamic nuclei that could be affected more than others. However, the dynamic of their changes during MS evolution and the mechanisms driving their differential alterations are still uncertain. METHODS: We paired a large cohort of 1,123 patients with MS with the same number of healthy controls, all scanned with conventional 3D-T1 MRI. To highlight the main atrophic regions at the thalamic nuclei level, we validated a segmentation strategy consisting of deep learning-based synthesis of sequences, which were used for automatic multiatlas segmentation. Then, through a lifespan-based approach, we could model the dynamics of the 4 main thalamic nuclei groups. RESULTS: All analyses converged toward a higher rate of atrophy for the posterior and medial groups compared with the anterior and lateral groups. We also demonstrated that focal MS white matter lesions were associated with atrophy of groups of nuclei when specifically located within the associated thalamocortical projections. The volumes of the most affected posterior group, but also of the anterior group, were better associated with clinical disability than the volume of the whole thalamus. DISCUSSION: These findings point toward the thalamic nuclei adjacent to the third ventricle as more susceptible to neurodegeneration during the entire course of MS through potentiation of disconnection effects by regional factors. Because this information can be obtained even from standard T1-weighted MRI, this paves the way toward such an approach for future monitoring of patients with MS.

Glymphatic system dysfunction predicts amyloid deposition, neurodegeneration, and clinical progression in Alzheimer's disease.

INTRODUCTION: Although glymphatic function is involved in Alzheimer's disease (AD), its potential for predicting the pathological and clinical progression of AD and its sequential association with core AD biomarkers is poorly understood. METHODS: Whole-brain glymphatic activity was measured by diffusion tensor image analysis along the perivascular space (DTI-ALPS) in participants with AD dementia (n = 47), mild cognitive impairment (MCI; n = 137), and normal controls (n = 235) from the Alzheimer's Disease Neuroimaging Initiative. RESULTS: ALPS index was significantly lower in AD dementia than in MCI or controls. Lower ALPS index was significantly associated with faster changes in amyloid positron emission tomography (PET) burden and AD signature region of interest volume, higher risk of amyloid-positive transition and clinical progression, and faster rates of amyloid- and neurodegeneration-related cognitive decline. Furthermore, the associations of the ALPS index with cognitive decline were fully mediated by amyloid PET and brain atrophy. DISCUSSION: Glymphatic failure may precede amyloid pathology, and predicts amyloid deposition, neurodegeneration, and clinical progression in AD. HIGHLIGHTS: The analysis along the perivascular space (ALPS) index is reduced in patients with Alzheimer's disease (AD) dementia, prodromal AD, and preclinical AD. Lower ALPS index predicted accelerated amyloid beta (Aß) positron emission tomography (PET) burden and Aß-positive transition. The decrease in the ALPS index occurs before cerebrospinal fluid Aß42 reaches the positive threshold. ALPS index predicted brain atrophy, clinical progression, and cognitive decline. Aß PET and brain atrophy mediated the link of ALPS index with cognitive decline.

Cognitive phenotype and neurodegeneration associated with Tau in Huntington's disease.

OBJECTIVE: The clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity, the present study delves into the association between Tau pathology and more severe cognitive phenotypes and brain damage in HD. METHODS: We used a comprehensive neuropsychological examination to characterize the cognitive phenotype of a sample of 30 participants with early-to-middle HD for which we also obtained 3 T structural magnetic resonance image (MRI) and cerebrospinal fluid (CSF). We quantified CSF levels of neurofilament light chain (NfL), total Tau (tTau), and phosphorylated Tau-231 (pTau-231). Thanks to the cognitive characterization carried out, we subsequently explored the relationship between different levels of biomarkers, the cognitive phenotype, and brain integrity. RESULTS: The results confirmed that more severe forms of cognitive deterioration in HD extend beyond executive dysfunction and affect processes with clear posterior-cortical dependence. This phenotype was in turn associated with higher CSF levels of tTau and pTau-231 and to a more pronounced pattern of posterior-cortical atrophy in specific brain regions closely linked to the cognitive processes affected by Tau. INTERPRETATION: Our findings reinforce the association between Tau pathology, cognition, and neurodegeneration in HD, emphasizing the need to explore the role of Tau in the cognitive heterogeneity of the disease.

Identification of Distinct Brain MRI Phenotypes and Their Association With Long-Term Dementia Risk in Community-Dwelling Older Adults.

BACKGROUND AND OBJECTIVES: Individual brain MRI markers only show at best a modest association with long-term occurrence of dementia. Therefore, it is challenging to accurately identify individuals at increased risk for dementia. We aimed to identify different brain MRI phenotypes by hierarchical clustering analysis based on combined neurovascular and neurodegenerative brain MRI markers and to determine the long-term dementia risk within the brain MRI phenotype subgroups. METHODS: Hierarchical clustering analysis based on 32 combined neurovascular and neurodegenerative brain MRI markers in community-dwelling individuals of the Age-Gene/Environment Susceptibility Reykjavik Study was applied to identify brain MRI phenotypes. A Cox proportional hazards regression model was used to determine the long-term risk for dementia per subgroup. RESULTS: We included 3,056 participants and identified 15 subgroups with distinct brain MRI phenotypes. The phenotypes ranged from limited burden, mostly irregular white matter hyperintensity (WMH) shape and cerebral atrophy, mostly irregularly WMHs and microbleeds, mostly cortical infarcts and atrophy, mostly irregularly shaped WMH and cerebral atrophy to multiburden subgroups. Each subgroup showed different long-term risks for dementia (min-max range hazard ratios [HRs] 1.01-6.18; mean time to follow-up 9.9 ± 2.6 years); especially the brain MRI phenotype with mainly WMHs and atrophy showed a large increased risk (HR 6.18, 95% CI 3.37-11.32). DISCUSSION: Distinct brain MRI phenotypes can be identified in community-dwelling older adults. Our results indicate that distinct brain MRI phenotypes are related to varying long-term risks of developing dementia. Brain MRI phenotypes may in the future assist in an improved understanding of the structural correlates of dementia predisposition.

Indications for implant-supported rehabilitation of the posterior atrophic maxilla: A multidisciplinary consensus among experts in the field utilising the modified Delphi method.

PURPOSE: To establish consensus-driven guidelines that could support the clinical decision-making process for implant-supported rehabilitation of the posterior atrophic maxilla and ultimately improve long-term treatment outcomes and patient satisfaction. MATERIALS AND METHODS: A total of 33 participants were enrolled (18 active members of the Italian Academy of Osseointegration and 15 international experts). Based on the available evidence, the development group discussed and proposed an initial list of 20 statements, which were later evalu-ated by all participants. After the forms were completed, the responses were sent for blinded ana-lysis. In most cases, when a consensus was not reached, the statements were rephrased and sent to the participants for another round of evaluation. Three rounds were planned. RESULTS: After the first round of voting, participants came close to reaching a consensus on six statements, but no consensus was achieved for the other fourteen. Following this, nineteen statements were rephrased and sent to participants again for the second round of voting, after which a consensus was reached for six statements and almost reached for three statements, but no consensus was achieved for the other ten. All 13 statements upon which no consensus was reached were rephrased and included in the third round. After this round, a consensus was achieved for an additional nine statements and almost achieved for three statements, but no consensus was reached for the remaining statement. CONCLUSION: This Delphi consensus highlights the importance of accurate preoperative planning, taking into consideration the maxillomandibular relationship to meet the functional and aesthetic requirements of the final restoration. Emphasis is placed on the role played by the sinus bony walls and floor in providing essential elements for bone formation, and on evaluation of bucco-palatal sinus width for choosing between lateral and transcrestal sinus floor elevation. Tilted and trans-sinus implants are considered viable options, whereas caution is advised when placing pterygoid implants. Zygomatic implants are seen as a potential option in specific cases, such as for completely edentulous elderly or oncological patients, for whom conventional alternatives are unsuitable.

Enlarged choroid plexus in relapsing-remitting multiple sclerosis may lead to brain structural changes through the glymphatic impairment.

OBJECTIVES: To investigate the potential link among choroid plexus (CP) volume, glymphatic clearance and brain structural change in relapsing-remitting multiple sclerosis (RRMS) patients. MATERIALS AND METHODS: Sixty-five RRMS patients and 48 healthy controls (HC) underwent MRI examination. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) was calculated to reflect glymphatic system function. The brain structure volume and DTI-ALPS index were compared between RRMS and HC. The mediating effect of the DTI-ALPS index between CP volume and brain structural changes was further investigated. The longitudinal changes of brain structure and DTI-ALPS index were compared in 20 RRMS patients. RESULTS: Compared to HC, CP volume in RRMS was significantly increased (P < 0.001), and DTI-ALPS index was significantly decreased (P = 0.001). The volumes of white matter, thalamus, putamen and pallidum were significantly decreased in RRMS, and the volumes of lateral ventricle and third ventricle were increased. Mediation analysis showed DTI-ALPS index partially mediated the association between CP enlargement and deep gray matter (DGM) atrophy in RRMS, and between CP enlargement and ventricle enlargement. CP volume and DTI-ALPS index were also significantly correlated with Expanded Disability Status Scale (EDSS) (P = 0.006, P = 0.043). Notably, the variation of DTI_ALPS index during the follow-up period were significantly and negatively correlated with the variation of EDSS (P = 0.045). CONCLUSION: Enlarged CP volume and decreased DTI_ALPS index may be closely related to DGM atrophy and ventricular enlargement in RRMS, and may be potential imaging markers of clinical disability.

A new segmentation algorithm for peripapillary atrophy and optic disk from ultra-widefield Photographs1.

BACKGROUND AND OBJECTIVE: The prevalence of myopia and high myopia is increasing globally, underscoring the growing importance of diagnosing high myopia-related pathologies. While existing image segmentation models, such as U-Net, UNet++, ResU-Net, and TransUNet, have achieved significant success in medical image segmentation, they still face challenges when dealing with ultra-widefield (UWF) fundus images. This study introduces a novel automatic segmentation algorithm for the optic disc and peripapillary atrophy (PPA) based on UWF fundus images, aimed at assisting ophthalmologists in more accurately diagnosing high myopia-related diseases. METHODS: In this study, we developed a segmentation model leveraging a Transformer-based network structure, complemented by atrous convolution and selective boundary aggregation modules, to elevate the accuracy of segmenting the optic disc and PPA in UWF photography. The atrous convolution module adeptly manages multi-scale features, catering to the variances in target sizes and expanding the deep network's receptive field. Concurrently, the incorporation of the selective boundary aggregation module in the skip connections of the model significantly improves the differentiation of boundary information between segmentation targets. Moreover, the comparison of our proposed algorithm with classical segmentation models like U-Net, UNet++, ResU-Net, and TransUNet highlights its considerable advantages in processing UWF photographs. RESULTS: The experimental results show that, compared to the other four models, our algorithm demonstrates substantial improvements in segmenting the optic disc and PPA in UWF photographs. In PPA segmentation, our algorithm improves by 0.8% in Dice, 1.8% in sensitivity, and 1.3% in intersection over union (IOU). In optic disc segmentation, our algorithm improves by 0.3% in Dice, 0.6% in precision, and 0.4% in IOU. CONCLUSION: Our proposed method improves the segmentation accuracy of PPA and optic disks based on UWF photographs, which is valuable for diagnosing high myopia-related diseases in ophthalmology clinics.

Prospective, multicenter, uncontrolled study on the effectiveness and safety of a hyaluronic acid water-based vaginal lubricant in alleviating vaginal dryness and dyspareunia.

BACKGROUND: Vaginal dryness (VD) represents a significant concern affecting women across diverse life stages, encompassing both pre- and postmenopausal women at any age. Dyspareunia, defined by genital pain that can be experienced before, during, or after intercourse, is often associated with vaginal dryness. AIM: This study aimed to evaluate the effectiveness and safety of a water-based vaginal lubricant with hyaluronic acid to reduce sexual discomfort associated with vaginal dryness. METHODS: A prospective, multicenter, uncontrolled clinical investigation was conducted over a three-month period in women aged 18 years or older experiencing pain or difficulty during sexual intercourse for whom the use of a vaginal lubricant was recommended. RESULTS: Significant improvements were observed in the FSFI scores, indicating enhanced sexual function (p < .001). Vaginal dryness symptoms, including irritation, dryness, itching, and dyspareunia, significantly decreased after product use (p < .001). CLINICAL IMPLICATIONS: This study contributes to the limited scientific knowledge on the application of lubricants in the context of symptoms associated with VD. STRENGTHS & LIMITATIONS: In addition to the short study period, inherent limitations of the study design, and lack of placebo control, it is pertinent to acknowledge that some of the pros used in this study were not based on validated questionnaires. However, as far as we know, this study is the only one that analyzes well-being and sexual pleasure as results using a lubricant formulated with hyaluronic acid. CONCLUSION: This tested vaginal lubricant with hyaluronic acid has demonstrated efficacy in improving vaginal dryness and female sexual function, particularly in reducing pain and improving lubrication during sexual intercourse, and showed a favorable safety profile, with minimal and transient adverse events.

Can imaging determine if a rotator cuff tear is traumatic?

AIM: We reviewed the last decade of literature to update a previous publication on this topic by the senior author. In New Zealand, traumatic causation has implications for entitlement for treatment though the Accident Compensation Corporation (ACC). Acuity and chronicity may also be relevant in determining repairability. METHODS: Literature was reviewed regarding acromial morphology, greater tuberosity (GT) cysts, acromiohumeral interval (AHI), fatty degeneration and atrophy, acromioclavicular (AC) arthrosis, tendinopathy, bursal changes and other features. RESULTS: Some factors can be considered normal for those middle aged and older, including AC arthrosis, type 1 and 2 acromion and tendinopathy. Some factors may indicate acuity, including haemorrhage and debris, GT oedema, mid-substance soft tissue tear, kinking of the tendon and isolated complete subscapularis tears. Other factors may be associated with chronicity, including significant fatty degeneration, positive tangent sign for atrophy, anterior GT cysts, type 3 acromion, critical shoulder angle (CSA) >35 degrees and acromial index (AI) <0.7. CONCLUSION: A multitude of factors on imaging may infer, to a varying degree, the likelihood of acuity or chronicity. The patient history is also of importance in determining causation.

Plasma homocysteine level, estradiol level, and brain atrophy: a Mendelian randomization study.

OBJECTIVES: Observational studies link elevated plasma homocysteine (Hcy) with vascular disease. Our aim was to assess the gender difference in the association between the plasma tHcy level and brain atrophy and identify the possible influencer. We employed Mendelian randomization (MR) to explore the causal relationship between plasma tHcy level, estradiol level, and brain atrophy. METHODS: A total of 687 patients with brain atrophy were included, and gender-specific subgroup analyses in association between tHcy and brain atrophy are conducted. From genome-wide association studies, we selected genetic variants (P < 5 × 10-8) for the plasma tHcy level and estradiol level. We investigated the degree of brain atrophy (including gray matter volume and total brain volume) in the UK biobank (n = 7,916). The inverse variance-weighted and several sensitivity MR regression analyses were carried out. RESULTS: The plasma tHcy level was significantly associated with brain atrophy for females, but not for males. An MR study showed that there was little evidence of the causal link between elevated plasma tHcy and brain atrophy. On the other hand, we found evidence to support causality for genetically decreased estradiol with higher risk of brain atrophy. Furthermore, genetic predisposition to elevated plasma tHcy was associated with a lower estradiol level. CONCLUSIONS: The influence of estradiol on the association between tHcy and brain atrophy deserves further investigation.