Impairment In Patients Research Articles

Spatially Localized Visual Perception Estimation by Means of Prosthetic Vision Simulation

Retinal prosthetic devices aim to repair some vision in visually impaired patients by electrically stimulating neural cells in the visual system. Although there have been several notable advancements in the creation of electrically stimulated small dot-like perceptions, a deeper comprehension of the physical properties of phosphenes is still necessary. This study analyzes the influence of two independent electrode array topologies to achieve single-localized stimulation while the retina is electrically stimulated: a two-dimensional (2D) hexagon-shaped array reported in clinical studies and a patented three-dimensional (3D) linear electrode carrier. For both, cell stimulation is verified in COMSOL Multiphysics by developing a lifelike 3D computational model that includes the relevant retinal interface elements and dynamics of the voltage-gated ionic channels. The evoked percepts previously described in clinical studies using the 2D array are strongly associated with our simulation-based findings, allowing for the development of analytical models of the evoked percepts. Moreover, our findings identify differences between visual sensations induced by the arrays. The 2D array showed drawbacks during stimulation; similarly, the state-of-the-art 2D visual prostheses provide only dot-like visual sensations in close proximity to the electrode. The 3D design could offer a technique for improving cell selectivity because it requires low-intensity threshold activation which results in volumes of stimulation similar to the volume surrounded by a solitary RGC. Our research establishes a proof-of-concept technique for determining the utility of the 3D electrode array for selectively activating individual RGCs at the highest density via small-sized electrodes while maintaining electrochemical safety.

Electronic Documentation of Findings in Visual Impairment Counselling Using FIDUS Software

The increasing use of electronic documentation extends to consultation for the visually impaired. The aim of this project was to develop a set of forms and electronic patient records specifically for low vision care, giving equal consideration to ophthalmological, orthoptic, and optometric specialities, as well as teaching aspects. FIDUS software (FIDUS Arztservice Wente GmbH, Darmstadt, Germany) is a well-established tool in ophthalmology practices and clinics. The software was used as a basis to develop digital entry forms with features such as auto-fill, selection recommendations, and inventory management for visual aids. The aim of the project was to maximise clarity and ease of use while also saving time during consultation with visually impaired patients. This article presents the implementation of these criteria using the electronic FIDUS record card with the corresponding electronic forms for electronic patient records taken during consultation with visually impaired patients. The index card visualises the patient's most important data and findings at a glance. Specifically designed for low vision consultation, the examination form documents visual aids prescribed to the patient in detail while also saving time. Other forms enable direct printing of prescription recommendations, test reports, and certificates. Entry forms can also be printed out for conventional handwritten records. We have achieved an electronic patient record system specifically geared to ophthalmological and optical care requirements including local inventory for visually impaired patients. Determining the level of acceptance on the part of examiners, patients, and students and optimising the software will require follow-up studies.

Subjective spatial orientation discomfort is associated with decreased real-world spatial performance and lower cognitive function

BackgroundSpatial memory and orientation deficits often precede cognitive impairment in incipient dementia, e.g., Alzheimer’s disease. Therefore, early diagnosis of spatial impairment may be crucial to the initiation of an adequate therapeutic intervention. Subjective tests, such as spatial anxiety and spatial discomfort questionnaires, and objective tests in the form of quantitative measures of orientation, are available. In these tests, vestibular hypofunction has often been neglected as a potential confounder. The major research question in this study was how self-assessed questionnaires correlate with the data from objective measures in participants with proven normal vestibular function.MethodsA heterogeneous group of 135 participants (72 females, 63 males, mean age 62.75 ± 14.46 years) from a tertiary center for vertigo and balance disorders consisting of two cohorts, with (n = 49) and without (n = 86) cognitive deficits in a screening test (MoCA), was examined (a) with a newly introduced inventory for subjective spatial discomfort (Extended Inventory for Spatial Orientation Discomfort, EISOD), (b) a well-established questionnaire for subjective spatial skills (Santa Barbara Sense of Direction Scale, SBSODS), and (c) the objective three-dimensional real-world pointing task (3D-RWPT) before and after horizontal body rotations. In all patients, acute central or peripheral vestibular deficits were ruled out by neuro-orthoptics, bithermal water calorics and video head impulse testing.ResultsSelf-assessed spatial orientation discomfort (EISOD) correlated with the amount of spatial impairment in the 3D-RWPT for both cohorts. The cognitively impaired patients showed significantly higher levels of spatial discomfort (i.e., lower scores; Welch’s t-test t-2.58, p < 0.01, Cohen’s d − 0.46), and higher angular deviations in the (cognitively demanding) transformation paradigm of the 3D-RWPT (t 2.37, p 0.02, Cohen’s d 0.44). They preferred retinotopic/egocentric spatial encoding strategies in the pointing task (Welch’s t-test t-2.61, p < 0.01, Cohen’s d − 0.47). In contrast, the self-report of spatial abilities (SBSODS) yielded no significant group differences (t − 1.66, p 0.10) and was not reliably associated with objective accuracy in the pointing task.ConclusionIn patients without vestibular deficits, subjective spatial discomfort (EISOD) correlated with the accuracy in an objective 3D-pointing task for both cohorts, and higher discomfort was associated with more severe cognitive impairment. EISOD-scores showed higher correlation indices than a self-report of spatial skills using the SBSODS. When investigating spatial abilities in patients with suspected cognitive impairment, it appears reasonable that both subjective spatial discomfort, subjective spatial abilities, and objective spatial measures should be combined. Future research in patients with vestibular dysfunction is needed to understand the role of vestibular deficits for the development of spatial orientation discomfort.

Comorbidity Pattern and Autonomic Nervous System Dysfunction in Patients with Chronic Vulvar Discomfort

This study examines novel concepts of comorbidity in patients with chronic vulvar discomfort using data from the DATRIV (Diagnostic Accuracy of Three Rings Vulvoscopy) study, which involved 328 participants categorized into four groups: asymptomatic individuals with normal or impaired vulvar skin and patients with chronic vulvar discomfort, classified as either vulvodynia or vulvar dermatosis. Clinical data were collected through a structured questionnaire and analyzed using statistical software, including StatSoft (Dell, Austin, TX, USA), Statistica 12 (TIBCO®, Palo Alto, CA, USA), and SPSS 20 (IBM, Armonk, NY, USA). The study received approval from the Institutional Review Board of Polyclinic Harni, and all participants provided written informed consent. The findings reveal significantly higher comorbidity rates in patients with chronic vulvar discomfort compared to other groups (p = 0.0000). A substantial percentage of asymptomatic participants with both normal (63.4%) and impaired (70.7%) vulvar skin also reported comorbid conditions. Analysis of comorbidity curves revealed distinct patterns of symptom progression, with a gradual increase in frequency from asymptomatic individuals to patients with vulvodynia, followed by a decline in vulvar dermatosis cases. These patterns highlight the central role of autonomic nervous system (ANS) dysfunction, where sympathetic hyperactivity and parasympathetic depression contribute to separate comorbidity chains. These dysfunctions may act independently or concurrently, leading to various health issues. The elevated comorbidity rates and overlapping symptomatology suggest complex pathophysiology driven by ANS dysregulation. Further research on comorbidity clusters may unveil new therapeutic targets and guide the development of multifaceted treatment strategies.

Energy Associated With Dynamic Network Changes in Patients With Multiple Sclerosis and Cognitive Impairment.

Patients with multiple sclerosis (MS) often experience cognitive impairment, and this is related to structural disconnection and subsequent functional reorganization. It is unclear how specific patterns of functional reorganization might make it harder for cognitively impaired (CI) patients with MS to dynamically adapt how brain regions communicate, which is crucial for normal cognition. We aimed to identify dynamic functional network patterns that are relevant to cognitive impairment in MS and investigate whether these patterns can be explained by altered energy costs. Resting-state functional and diffusion MRI was acquired in a cross-sectional design, as part of the Amsterdam MS cohort. Patients with clinically definitive MS (relapse-free) were classified as CI (≥2/7 domains Z < -2), mildly CI (MCI) (≥2/7 domains Z < -1.5), or cognitively preserved (CP) based on an expanded Brief Repeatable Battery of Neuropsychological Tests. Functional connectivity states were determined using k-means clustering of moment-to-moment cofluctuations (i.e., edge time series), and the resulting state sequence was used to characterize the frequency of transitions. Control energy of the state transitions was calculated using the structural network with network control theory. Imaging and cognitive data were available for 95 controls and 330 patients (disease duration: 15 years; 179 CP, 65 MCI, and 86 CI). We identified a "visual network state," "sensorimotor network state," "ventral attention network state," and "default mode network state." CI patients transitioned less frequently between connectivity states compared with CP (β = -5.78; p = 0.038). Relative to the time spent in a state, CI patients transitioned less from a "default mode network state" to a "visual network state" (β = -0.02; p = 0.004). The CI patients required more control energy to transition between states (β = 0.32; p = 0.007), particularly for the same transition (β = 0.34; p = 0.049). This study showed that it costs more energy for MS patients with cognitive impairment to dynamically change the functional network, possibly explaining why these transitions occur less frequently. In particular, transitions from a default mode network state to a visual network state were relevant for cognition in these patients. To further study the order of events leading to these network disturbances, future work should include longitudinal data across different disease stages.

Drug prescriptions in elderly hospitalized patients with cognitive impairment in the Italian Dementia Friendly Hospital project

ObjectiveThe aim of the study was to characterize drug prescription patterns in elderly patients hospitalized in acute wards as a function of cognitive status and staff training.MethodsWe recorded clinical parameters reflecting health status and drug prescriptions at admission, during hospital stay, and at discharge before and after a short staff training on the needs of aged cognitively impaired patients. Participants aged 65 and older had a Mini-Mental State Examination (MMSE) score ≥16. The number of prescriptions, sedative and anticholinergic load, and drug–drug interactions were evaluated. Of the 116 older patients analyzed, 59 patients were cognitively impaired, and 57 were cognitively normal with an MMSE value &amp;gt; 24. Fifty-nine patients (28 CN, 31 CI) were assisted by the hospital health staff after training.ResultsParticipants presented a widespread polypharmacy. Cognitively impaired patients received more prescriptions, more inappropriate prescriptions, had a greater sedative load, and were exposed to more interactions. Staff training had no effect on the prescription pattern.ConclusionThe results suggest that hospitalized cognitively impaired patients are overprescribed psychotropic drugs and have an excessive sedative and anticholinergic load. Interventions designed to improve dementia care practices in health staff that are not also designed to manage drug polypharmacy do not modify prescription patterns.

NIMG-57. EMBEDDED GRAPH DERIVED FROM PSEUDO-RESTING-STATE FUNCTIONAL MRI CAN PREDICT COGNITIVE IMPAIRMENT IN GLIOMA

Abstract Resting-state brain network analyses are of great interest in studying the neurocognition and measuring the functional connectivity (FC) patterns of glioma patients. However, resting-state functional MRI (rs-fMRI) is not assessed in clinical routine due to the scan time and cost. The current study used pseudo-resting-state functional MRI (pseudo-rs-fMRI) derived from dynamic susceptibility contrast (DSC) perfusion MRI to predict cognitive impairment in glioma. 37 glioma patients were enrolled consecutively in the current study with DSC perfusion MRI acquired and neurocognition assessed, where 24 glioma patients also got rs-fMRI collected. The pseudo-rs-fMRI was created by voxel-wise subtracting the Gamma-variate modeled signal of contrast agent bolus from the original DSC perfusion signal. Following the pre-processing of pseudo-rs-fMRI and full rs-fMRI, the functional connectivity network (FCN) was established for each patient. Graph embedding was implemented to learn and extract features of each node in the binarized FCN, and the decision tree classification algorithm was applied to distinguish cognitive impairment. FCNs of 24 patients with DSC perfusion and rs-fMRI acquired were used to train the model, and FCNs of 13 patients with only DSC perfusion MRI acquired were used to test the model. The AUC (area under the receiver operating characteristic curve) was used to evaluate the model’s performance. The similarity and mean-square-difference between average FCNs extracted from rs-fMRI and pseudo-rs-fMRI were 0.6769 and 0.0263, respectively. Classifier trained using 24 FCNs of pseudo-rs-fMRI has an AUC of 0.750 in identifying cognitively impaired patients in the testing cohort. Combining FCNs of both rs-fMRI and pseudo-rs-fMRI to train the classifier resulted in a higher AUC of 0.833 in the testing cohort. To summary, DSC perfusion MRI-derived pseudo-rs-fMRI can be used to predict cognitive impairment in patients with gliomas. External validation would be required.

Dynamin-1 is a potential mediator in cancer-related cognitive impairment

Dynamin-1 (DNM1) is crucial for synaptic activity, neurotransmission, and associative memory, positioning it as a potential biomarker of cancer-related cognitive impairment (CRCI), a neurological consequence of cancer treatment characterized by memory loss, poor concentration, and impaired executive function. Through a stepwise approach, this study investigated the role of DNM1 in CRCI pathogenesis, incorporating both human data and animal models. The human study recruited newly diagnosed, chemotherapy-naïve adolescent and young adult cancer and non-cancer controls to complete a cognitive instrument (FACT-Cog) and blood draws for up to three time points. Following that, a syngeneic young-adult WT (C57BL/6) female mouse model of breast cancer chemobrain was developed to study DNM1 expression in the hippocampus. Samples from eighty-six participants with 30 adolescent and young adult (AYA) cancer and 56 non-cancer participants were analyzed. DNM1 levels were 32 ​% lower (P ​= ​0.041) among cancer participants compared to non-cancer prior to treatment. After receiving cytotoxic treatment, cognitively impaired cancer patients were found to have 46 ​% lower DNM1 levels than those without impairment (P ​= ​0.049). In murine breast cancer-bearing mice receiving chemotherapy, we found a greater than 40 ​% decline (P ​< ​0.0001) in DNM1 immunoreactivity in the hippocampal CA1 and CA3 subregions concurrent with a deterioration in spatial recognition memory (P ​< ​0.02), compared to control mice without exposure to cancer and chemotherapy. Consistently observed in both human and animal studies, the downregulation of DNM1 is linked with the onset of CRCI. DNM1 might be a biomarker and therapeutic target for CRCI.

The funnel effect of reserves prompted by leisure activities across the Alzheimer's disease continuum.

Reserves' mechanisms explain inconsistencies between accumulation of neuropathological damage and clinical manifestations. Leisure activities are believed to promote reserves. This study evaluates whether cognitive, social, and physical leisure activities performed over life-span predict current cognitive functioning in normal aging and Alzheimer's disease (AD) continuum. 35 AD, 24 amnestic-Mild Cognitive Impairment (a-MCI) patients, 21 individuals with subjective cognitive complaint (SCD), and 25 controls underwent a questionnaire developed to quantify leisure activities in different life periods, the Addenbrooke's Cognitive Examination-Revised (ACE-R), and T1-weighted 3T-MRI scans for brain volumetrics and cortical thickness quantification. Partial/total leisure activities' scores and demographic and brain variables were entered as predictors, while ACE-R scores as dependent variables in linear regression analyses. Current level of cognition was predicted by (i) social and physical activities performed in middle age and current cognitive activity in AD; (ii) cognitive and social activities performed in middle age, current age and cortical thickness in a-MCI; (iii) recreational activities the set of lifetime, current age, and brain features in SCD; (iv) education and the set of lifetime leisure activities over lifespan in controls. This study shows a funnel effect due to gradual reduction of stimulatory activities in the transition from healthy aging to AD. Reserve indices taking into account different types of stimulatory activities allow to capture even smallest residual effects of reserves accumulated over lifespan, until their complete depletion at advanced AD stages. These results may help target tailored interventions during normal and pathological aging.

Blood biomarkers for Alzheimer’s disease with the Lumipulse automated platform: Age-effect and clinical value interpretation

BackgroundAdvances in analytical methods have recently paved the way to Alzheimer’s disease (AD) biomarkers testing in blood along with the more established CSF testing. To ensure a forthcoming application of this low-invasive diagnostic that might allow to recognize early onset of dementia, appropriate pathological cut-points need to be defined. MethodsIn this cross-sectional study we measured blood and CSF neurofilament light chain (NFL), phosphorylated tau (pTau 181), Amyloid-β1-42 (AB 1–42) and Amyloid-β1-40 (AB 1–40) on a fully automated chemiluminescent platform (Lumipulse, Fujirebio) in 80 cognitively impaired patients and 55 cognitively unimpaired subjects. Clinical cut points were calculated with receiver-operator characteristic (ROC) curve analysis and a head-to-head comparison of blood and CSF testing was performed. ResultsBlood NFL best discriminant thresholds to distinguish neurodegenerative diseases from controls varied age-dependently, being 19 and 33 pg/mL in subjects 50–65 years and > 65 years respectively. AD was best framed by AB 1–42/1–40 ratio < 0.079 and ptau181 > 1 pg/mL. Though a strong correlation for all biomarkers, only blood AB ratio was equal to CSF testing for AD diagnosis. ConclusionsThe specific context of use might be considered to define the cut-offs of blood biomarkers of neurodegenerative diseases. Future efforts towards reference materials for each AD blood biomarker will improve clinical cut-offs.

Effectiveness of Dynamic Neuromuscular Stabilization Technique in Neurological Conditions: An Updated Review

Abstract Objective This updated review aims to identify the effectiveness of dynamic neuromuscular stabilization (DNS) techniques in neurological conditions. Method A literature search was carried out from 2013 to 2024 on PubMed, Google Scholar, Research Gate, and Scopus databases. Following keywords were used to identify the relevant articles such as dynamic neuromuscular stabilization, reflex-mediated DNS, neurological conditions, DNS, cerebral palsy, stroke, Parkinson's disease, multiple sclerosis, neurodegenerative conditions, ataxia, Alzheimer's disease, and multiple sclerosis with Boolean operators. All the full-text, English-written articles based on inclusion and exclusion criteria were included in the review irrespective of their experiment study design, only the review article was excluded. Results This updated review included 10 articles related to neurological conditions including, stroke, multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebral palsy. The results show significant differences in various outcome measures of the included studies. Conclusion The findings suggest that DNS is an effective approach to use in the rehabilitation protocol of neurologically impaired patients and is beneficial in improving their health outcomes and overall quality of life. This review concludes that more evidence is required in this area of research with good quality research and long follow-up periods.

Association between trace elements and cognitive function among hemodialysis patients in Turkey.

Cognitive impairment is common among patients with hemodialysis. Hemodialysis patients have theoretical risks for both deficiency and accumulation of trace elements. We aimed to investigate the relationship between cognitive dysfunction and whole blood levels of trace elements in hemodialysis patients. We also aimed to examine the effect of baseline trace element status and cognitive dysfunction on mortality. Maintenance hemodialysis patients and age-and sex-matched controls were included. The whole blood levels of trace elements were measured by inductively coupled plasma mass spectrometry. Cognitive impairment was defined as a score of ≤24 points on the Montreal Cognitive Assessment test. Executive dysfunction was also defined as Trails A score of more than 75 s and Trails B score of more than 180 s. Forty-two patients and 35 controls were included. Cognitive impairment was detected in 69% of the patients and 45.7% of the controls (p = 0.039). Cognitively impaired patients had lower education years (p = 0.003) and higher whole blood levels of manganese (Mn) and lead (Pb) (p = 0.026, p = 0.019, respectively) compared to patients without cognitive impairment. Mn levels were also found statistically higher in patients with executive dysfunction compared to patients without executive dysfunction (p = 0.005). Lower education years and higher Pb levels were independent risk factors for cognitive impairment in hemodialysis patients (odds ratio [OR] 0.589 [95% confidence interval, CI 0.400-0.866, p = 0.007] and OR 1.047 [95% CI 1.001-1.096, p = 0.047, respectively]). Cognitive impairment, especially impaired executive function, is common among patients with hemodialysis patients. Cognitive impairment is not found to be associated in cross-sectional analysis with several modifiable end-stage renal disease- and dialysis-associated factors. The accumulation of trace elements especially Mn and Pb might exacerbate the cognitive dysfunction in hemodialysis patients.

Clinical usefulness of the Verbal Fluency Index (VFI) in amyotrophic lateral sclerosis.

This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients. N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency - S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60"-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale - Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores. The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score - regardless of whether they presented or not with a below-cutoff NoW - reported worse ECAS-Executive scores than NoW + VFI + ones. The present reports support the use of the Italian VFI as a mean to validly assess ALS patients' executive status by limiting the effect of motor disabilities that might undermine their speech rate.

Surgical Management for Boutonniere Disease

Boutonniere disease is a hand injury causing extension lag or restriction in the proximal interphalangeal joint and hyperextension in the distal interphalangeal joint. This condition often arises from direct laceration or closure damage to the central tendon, rheumatoid arthritis, osteoarthritis, Dupuytren contracture, pulley injury, burns, and other conditions. Surgical management for Boutonniere deformity relies on the expertise of the attending physician and involves both non-surgical and surgical options. In acute cases, conservative therapy should be pursued, while in chronic cases, conservative management may be advised. Surgical intervention is used to transform excessive extension force of the distal interphalangeal joint into extension force of the proximal interphalangeal joint. This is necessary to heal an open rupture of the central tendon. Surgical techniques for chronic deformity are complex due to variables and hand surgeons' expertise. There is no definitive surgical therapy for persistent buttonhole deformity, but several approaches have been documented in case studies. These include terminal tenotomy, collateral band surgery, central tendon surgery, tendon transfer and grafting, stepwise extension mechanism readjustment surgery, and arthrodesis. Central tendon surgery addresses the central tendon, where injured tissue transforms into scar tissue, resulting in delayed extension of the proximal interphalangeal joint. Tendon transfer or grafting have been documented for rotator cuff mechanism rehabilitation, but no definitive guidance exists for these techniques. Curtis treatment introduced a sequential therapy approach for traumatic buttonhole deformity, which involves splinting, excising the transverse reticular ligament, resecting and lengthening the collateral ligament, and repositioning the core tendon. Arthrodesis may be applicable in cases of advanced arthritis, coronal plane deformity, functional impairment, or elderly patients. There are no definitive indications for surgical interventions for persistent buttonhole deformity, and outcomes may be variable or inferior. Understanding the deformity, its progression, and patient's functional constraints is crucial for effective treatment

Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease.

Current AT(N) stratification for Alzheimer's disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.

Association of Normative and Non-Normative Brain Networks With Cognitive Function in Patients With Temporal Lobe Epilepsy.

Despite their temporal lobe pathology, a significant subgroup of patients with temporal lobe epilepsy (TLE) is able to maintain normative cognitive functioning. In this study, we identify patients with TLE with intact vs impaired neurocognitive profiles and interrogate for the presence of both normative and highly individual intrinsic connectivity networks (ICNs)-all toward understanding the transition from impaired to intact neurocognitive status. This retrospective cross-sectional study included patients with TLE and matched healthy controls (HCs) from the Thomas Jefferson Comprehensive Epilepsy Center. Functional MRI data were decomposed using independent component analysis to obtain individualized ICNs. In this article, we calculated the degree of match between individualized ICNs and canonical ICNs (e.g., 17 resting-state networks by Yeo et al.) and divided each participant's ICNs into normative or non-normative status based on the degree of match. 100 patients with TLE (mean age 42.0 [SD: 13.7] years, 47 women) and 92 HCs were included in this study. We found that the individualized networks matched to the canonical networks less well in the cognitively impaired (n = 24) compared with the cognitively intact (n = 63) patients with TLE by 2-way mixed-measures analysis of variance (impaired vs intact mean difference [MD] -0.165 [-0.317, -0.013], p = 0.028). The cognitively impaired patients showed significant abnormalities in the profiles of both normative (impaired vs intact MD -0.537 [-0.998, -0.076], p = 0.017, intact vs HC MD -0.221 [-0.536, 0.924], p = 0.220, and impaired vs HC MD -0.759 [-1.200, -0.319], p < 0.001) and non-normative networks (impaired vs intact MD 0.484 [0.030, 0.937], p = 0.033, intact vs HC MD 0.369 [0.059, 0.678], p = 0.014, and impaired vs HC MD 0.853 [0.419, 1.286], p < 0.001) while the intact patients showed abnormalities only in non-normative networks. At the same time, we found that normative networks held a strong, positive association with the neuropsychological measures, with this association negative in non-normative networks. Our data demonstrated that significant cognitive deficits are associated with the status of both canonical and highly individual ICNs, making clear that the transition from intact to impaired cognitive status is not simply the result of disruption to normative brain networks.

Structural disruption in subjective cognitive decline and mild cognitive impairment.

Subjective cognitive decline (SCD) marks the initial stage in Alzheimer's disease continuum. Nonetheless, current research findings regarding brain structural changes in the SCD are inconsistent. In this study, 37 SCD patients, 28 mild cognitive impairment (MCI) patients, and 42 healthy controls (HC) were recruited to investigate structural alterations. Morphological and microstructural differences among the three groups were analyzed based on T1- and diffusion-weighted images, correlating them with neuropsychological assessments. Additionally, classification analysis was performed by using support vector machines (SVM) categorize participants into three groups based on MRI features. Both SCD and MCI showed decreased volume in left inferior parietal lobe (IPL) compared to HC, while SCD showed altered morphologies in the right inferior temporal gyrus (ITG), right insula and right amygdala, and microstructures in fiber tracts of the right ITG, lateral occipital cortex (LOC) and insula relative to MCI. Moreover, the volume in the left IPL, right LOC, right amygdala and diffusivity value in fiber tracts of right LOC were significantly correlated with cognitive functions across all subjects. The classification models achieved an accuracy of > 0.7 (AUC = 0.8) in distinguishing the three groups. Our findings suggest that SCD and MCI share similar atrophy in the IPL but show more differences in morphological and microstructural features of cortical-subcortical areas.

Genetic and clinical correlates of two neuroanatomical AI dimensions in the Alzheimer’s disease continuum

Alzheimer’s disease (AD) is associated with heterogeneous atrophy patterns. We employed a semi-supervised representation learning technique known as Surreal-GAN, through which we identified two latent dimensional representations of brain atrophy in symptomatic mild cognitive impairment (MCI) and AD patients: the “diffuse-AD” (R1) dimension shows widespread brain atrophy, and the “MTL-AD” (R2) dimension displays focal medial temporal lobe (MTL) atrophy. Critically, only R2 was associated with widely known sporadic AD genetic risk factors (e.g., APOE ε4) in MCI and AD patients at baseline. We then independently detected the presence of the two dimensions in the early stages by deploying the trained model in the general population and two cognitively unimpaired cohorts of asymptomatic participants. In the general population, genome-wide association studies found 77 genes unrelated to APOE differentially associated with R1 and R2. Functional analyses revealed that these genes were overrepresented in differentially expressed gene sets in organs beyond the brain (R1 and R2), including the heart (R1) and the pituitary gland, muscle, and kidney (R2). These genes were enriched in biological pathways implicated in dendritic cells (R2), macrophage functions (R1), and cancer (R1 and R2). Several of them were “druggable genes” for cancer (R1), inflammation (R1), cardiovascular diseases (R1), and diseases of the nervous system (R2). The longitudinal progression showed that APOEε4, amyloid, and tau were associated with R2 at early asymptomatic stages, but this longitudinal association occurs only at late symptomatic stages in R1. Our findings deepen our understanding of the multifaceted pathogenesis of AD beyond the brain. In early asymptomatic stages, the two dimensions are associated with diverse pathological mechanisms, including cardiovascular diseases, inflammation, and hormonal dysfunction—driven by genes different from APOE—which may collectively contribute to the early pathogenesis of AD. All results are publicly available at https://labs-laboratory.com/medicine/.

Immune Checkpoint Blockade Therapies Efficacy and Toxicity in Patients With Impaired Renal Function in Metastatic Bladder Cancer

BackgroundIn this study, we reported the real-life results of data from impaired renal patients with urothelial carcinoma who were treated with ICTs. MethodsThe patients were categorized into 3 different groups GFR ≥60mL/min (normal), 60mL/min-30mL/min (low), and less than 30 mL/min (very low) based on GFR. The primary endpoints were the overall response rate (ORR), overall survival (OS), duration of response with ICT, and safety. Median follow-up and OS were estimated by using the Kaplan-Meier method. ResultsOne hundred-five (60.3%) of patients were GFR normal, 26.4% were GFR low with 30mL/min-60mL/min, and 13.2% were very low group. ORR for GFR normal, low and very low groups were 36% (n = 38), 26% (n = 12) and %31 (7); P = .2, respectively. The median duration of response for GFR normal, low and very low groups were 47.2 months (95% CI, 24.5-51.4), 33.1 months (95% CI, 26.9-47), and 23.5 months (95% CI, 12.2-43.7); P = .01, respectively. The Median OS rate for GFR normal, low and very low groups were 11.9 (7.2-16.5) months, 4.7 (1.8-7.7) and 6.8 (1.1-13.6) months, P = .015, respectively. In addition, GFR <60 ml/min HR = 1.6; 95% CI 1.12-1.80; P = .02, maintained a significant association with OS in multivariate analysis. ConclusionsLong-term follow-up of real-world data confirms that the overall survival rate and durable response rate with ICT were higher in patients with GFR >60mL/min. On the other hand, we demonstrated that ICT was effective and a durable response seen in a group of patients with renal inpairement who did not have an effective systemic treatment option.

Disentangling gray matter atrophy and its neurotransmitter architecture in drug-naïve Parkinson's disease: an atlas-based correlation analysis.

Parkinson's disease is characterized by multiple neurotransmitter systems beyond the traditional dopaminergic pathway, yet their influence on volumetric alterations is not well comprehended. We included 72 de novo, drug-naïve Parkinson's disease patients and 61 healthy controls. Voxel-wise gray matter volume was evaluated between Parkinson's disease and healthy controls, as well as among Parkinson's disease subgroups categorized by clinical manifestations. The Juspace toolbox was utilized to explore the spatial relationship between gray matter atrophy and neurotransmitter distribution. Parkinson's disease patients exhibited widespread GM atrophy in the cerebral and cerebellar regions, with spatial correlations with various neurotransmitter receptors (FDR-P < 0.05). Cognitively impaired Parkinson's disease patients showed gray matter atrophy in the left middle temporal atrophy, which is associated with serotoninergic, dopaminergic, cholinergic, and glutamatergic receptors (FDR-P < 0.05). Postural and gait disorder patients showed atrophy in the right precuneus, which is correlated with serotoninergic, dopaminergic, gamma-aminobutyric acid, and opioid receptors (FDR-P < 0.05). Patients with anxiety showed atrophy in the right superior orbital frontal region; those with depression showed atrophy in the left lingual and right inferior occipital regions. Both conditions were linked to serotoninergic and dopaminergic receptors (FDR-P < 0.05). Parkinson's disease patients exhibited regional gray matter atrophy with a significant distribution of specific neurotransmitters, which might provide insights into the underlying pathophysiology of clinical manifestations and develop targeted intervention strategies.