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Spliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer\u27s disease
No full textDefault mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer\u27s disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V-VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a significant increase in pS5-RNA pol II levels in FC NCI, U1-70K in PreC MCI and mAD, and hnRNPA2B1 and SRSF2 levels in PCC mAD. 1N3Rtau levels were significantly increased in FC, decreased in PreC in mAD, and unchanged in PCC, whereas 1N4Rtau increased in mAD across the hubs. SRSF2, U1-70K, U1A, and hnRNPA2B1 nuclear optical density (OD), size, and number were unchanged across groups in FC and PCC, while PreC OD hnRNPA2B1 was significantly greater in mAD. Mislocalized U1A and U1-70K tangle-like structures were found in a few PCC cases and colocalized with AT8-bearing neurofibrillary tangles (NFTs). FC pS5-RNA pol II, PreC U1-70K, Pre pS5,2-RNA pol II, and PCC hnRNPA2B1 and SRSF2 protein levels were associated with cognitive decline but not neuropathology across clinical groups. By contrast, splicing protein nuclear OD measures, size, counts, and mislocalized U1-70K and U1A NFT-like structures were not correlated with NFT or plaque density, cognitive domains, and neuropathological criteria in DMN hubs. Findings suggest that RNA splicing protein alterations and U1 mislocalization contribute differentially to DMN pathogenesis and cognitive deterioration in AD
Awake Craniotomy for Eloquent Brain Arteriovenous Malformations: A Systematic Review and Individual Patient Data Meta-Analysis
No full textBACKGROUND: Arteriovenous malformations (AVMs) pose a risk of neurologic deterioration, particularly when located in eloquent areas. While awake surgery is well-established for treating low-grade gliomas near eloquent areas, its efficacy for AVMs is less conclusively reported. METHODS: This study conducted a systematic review and individual patient data meta-analysis following Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Literature searches were performed in PubMed, Embase, and Web of Science. Eligible studies included case reports, case series, retrospective or prospective cohorts, and randomized trials evaluating awake craniotomy (AC) for AVMs. Single proportion analysis with 95% confidence intervals (CIs) was utilized to pool the data. Case series and case reports were put together as a unique cohort. RESULTS: An analysis of 20 studies encompassing 287 patients was performed. The individual patient data cohort had 53 patients. The primary outcome pooled analysis indicated an 88% (95% CI: 81%-95%; I2=63%) rate of total resection. Moreover, a rate of nearly 12% (95% CI: 5%-19%; I2=63%) of subtotal resection was observed. Furthermore, the analysis unveiled a 20% (95% CI: 13%-28%; I2=58%) rate of postoperative neurological deficits, alongside a 6% (95% CI: 3%-9%; I2=29%) rate of follow-up neurological deficits. The mean hospital stay was 4.13 (95% CI: 3.61-4.66; I2=73%) days. CONCLUSIONS: AC for eloquent AVMs showed promising results. A significant rate of postoperative neurological deficits was found, which was reduced at follow-up. A small mean length of hospitalization was also found. These results suggest that AC for AVMs should be considered in eloquent lesion cases
Application of deformity principles in the management of spinal neoplasms: A Primer
No full textBACKGROUND: With advances in surgical techniques, radiation, and systemic therapy, prognoses and quality of life have improved amongst patients with primary and metastatic vertebral column tumors. Sagittal deformity is known to have an adverse impact on patient quality of life but has been largely ignored in this study population. METHODS: A comprehensive literature review was conducted, focusing on articles germane to the study of spinal deformity in the context of oncologic disease. Articles included those focusing on bone health, the association of spinal deformity with oncologic spine disease, and both pelvic and anterior column reconstruction in patients treated for primary tumors. RESULTS: Little to date has focused specifically on the management of spinal deformity in the context of spinal tumors. However, it is known that tumor involvement of the vertebral column is associated with poorer screw purchase, which can be further worsened by radiotherapy. Instrumentation techniques that seek to address underlying deformity must also balance the need for radiographic follow-up, which is improved with novel carbon fiber-reinforced polyetheretherketone implants, and the need for intraoperative contouring. Last, residual deformity is associated with poorer patient reported outcomes and increased mechanical complications in adult spinal deformity, but better study within the spinal oncology population is merited. CONCLUSION: The potential negative impact of spinal deformity on patient quality of life in the spinal oncology population is now better appreciated amongst spinal oncologists, but studies have been limited to date. Further investigation is merited as survival outcomes continue to improve
Magnetic Resonance Imaging-Based Assessment of Bone Quality Using Vertebral Bone Quality (VBQ) Scores in Spine Surgery-A Critical Assessment and Narrative Review
No full textBone health is a key determinant of success in spine surgery, making preoperative assessment of bone quality essential to optimal surgical risk stratification. Magnetic resonance imaging (MRI)-based vertebral bone quality (VBQ) score offers a novel approach to assess bone health in spine surgery candidates. The ability of MRI to assess bone quality without exposure to ionizing radiation makes it a potentially advantageous alternative to other traditional measures of bone density. VBQ has additionally shown potential to predict adverse outcomes, such as fragility fractures, instrumentation failure, subsidence and proximal junctional kyphosis. Variations of VBQ, such as endplate bone quality, S1 VBQ, and cervical VBQ, provide targeted insights at specific anatomical regions and potentially enhance the predictive accuracy of VBQ. However, clinical application of VBQ is limited by variability in MRI systems, patient-specific factors, and lack of standardized threshold values. This review aims to critically evaluate VBQ scores as an opportunistic, MRI-based assessment of bone health and its potential role in predicting surgical outcomes. While VBQ may provide some valuable insights into bone health, its role in preoperative risk assessment likely remains supplementary and requires further research to establish clinical validity and optimal cutoffs
Alzheimer\u27s disease: Clinical trials to watch
No full textSecond-generation anti-amyloid therapies (ATTs) offer new options for early Alzheimer\u27s disease treatment, but with modest efficacy and documented adverse events. Here we highlight several ongoing clinical trials, aiming to develop therapeutic agents with higher efficacy and better safety profiles including third-generation ATTs, aggregation inhibitors, Sigma-1 receptor agonists, anti-tau antisense oligonucleotides, and GLP-1 receptor agonists
Development of Modified Japanese Versions of Questionnaires to Assess Physical and Cognitively Stimulating Activities
No full textINTRODUCTION: Lifestyle factors such as physical and cognitively stimulating activities may protect against various diseases. However, only a few simple and validated questionnaires assess the lifestyle factors in Japan. Thus, we aimed to create Japanese versions of such questionnaires for assessing physical and cognitively stimulating activities. This study examined their inter-rater reliability and test-retest reproducibility. METHODS: We developed a Japanese version of questionnaires by translating the English questionnaire that assesses the frequency of several physical and cognitively stimulating activities. Additionally, the Japanese version assesses the duration of engagement in physical activities, and we have added mental activities such as meditation and Zen practice. The inter-rater reliability and test-retest reproducibility of evaluating the frequency, duration, frequency × duration of each physical activity, and frequency of each cognitively stimulating activity were tested in healthy volunteers. RESULTS: The study included 48 participants aged 25-67 years. We observed good inter-rater reliability and test-retest reproducibility for the physical and cognitively stimulating activity questionnaires. As a pilot approach, we calculated the Total Physical Activity Score (metabolic equivalents·min/week) with an intraclass correlation coefficient (ICC) (2,1) of 0.818 (95% confidence interval, 0.698-0.894), indicating good test-retest reproducibility. CONCLUSIONS: The Japanese versions of questionnaires used to assess the frequency and duration of physical and cognitively stimulating activities generally have good inter-rater reliability and test-retest reproducibility. While introducing the duration of engagement might enable the estimation of the Total Physical Activity Score, further validation using objective measures of activities and other self-reported physical activity questionnaires is necessary, which is a limitation of this study
The longitudinal association between dyslipidemia and cognitive trajectory
No full textBackgroundThe literature on dyslipidemia and cognitive trajectories among cognitively unimpaired (CU) persons remains inconclusive.ObjectiveTo investigate the association between baseline dyslipidemia and change in global and domain specific (i.e., memory, language, attention/executive function, and visuospatial skills) cognition in a population-based setting and whether the association differs by sex, age, or APOE ɛ4 carrier status.MethodsWe conducted a longitudinal study derived from the Mayo Clinic Study of Aging, involving 4236 CU persons aged ≥ 50 years. We ran linear mixed-effect models to examine baseline dyslipidemia in predicting longitudinal cognitive global and domain-specific z-scores adjusted for age, sex, education, medical comorbidity, repeated cognitive testing, and APOE ɛ4. We examined interactions among dyslipidemia, years since baseline, and separately by sex, age, and APOE ɛ4 carrier status.ResultsOver a median follow-up period of 6.4 years, CU individuals with dyslipidemia showed faster decline in z-scores of all domains, i.e., memory, language, attention/executive function, visuospatial and global cognition relative to CU individuals without dyslipidemia. Three-way interactions showed that dyslipidemia\u27s effect on decline in z-scores of global cognition, attention and visuospatial skills was less pronounced in males than females. Higher age increased dyslipidemia\u27s effect on decline in z-scores of attention but not global cognition or any other domain. APOE ɛ4 carrier status did not modify the effect of dyslipidemia on cognitive z-scores.ConclusionsDyslipidemia was associated with faster global and domain-specific cognitive decline over time in older community-dwelling individuals who were cognitively unimpaired at baseline. The effect of dyslipidemia on cognitive trajectories may be sex-influenced
Time saved in activities of daily living and whole-brain volume: Post hoc analysis of a randomized feasibility trial of gamma oscillation treatment in participants with mild or moderate Alzheimer\u27s disease
No full textINTRODUCTION: Gamma oscillations in the brain are necessary for normal cognitive function, sensory processing, and memory consolidation, and are reduced in Alzheimer\u27s disease (AD). In a 6 month, randomized, feasibility trial in participants with mild-to-moderate AD (OVERTURE [NCT03556280], n = 76), a non-invasive method for sensory-evoked brain gamma oscillations outperformed sham on the secondary outcomes of slowing decline on the Alzheimer\u27s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) functional scale, magnetic resonance imaging measures of whole brain volume and the Mini-Mental State Examination (MMSE) cognitive outcome, despite not showing statistical significance on the primary outcome (Mild and Moderate Alzheimer\u27s Disease Composite [MADCOMS]), a composite cognitive-functional score. In this post hoc analysis of OVERTURE, we evaluated the effects of investigational sensory-evoked gamma oscillation treatment in terms of time saved, as an estimate of slowing in disease progression, on ADCS-ADL, MMSE, and whole-brain volume. METHODS: Disease trajectories based on the ADCS-ADL, MMSE, and whole-brain volume changes from baseline within each treatment group were constructed using mixed-effects models. Horizontal projection from active to sham arm yielded time saved from baseline at each visit. Data from the open label extension (OLE) phase of the OVERTURE study have also been used to analyze the time-saving effect of active treatment in an extended period. RESULTS: Compared to sham, time savings of 4.83, 4.59, and 4.09 months over 6 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed in the randomized controlled trial phase. When including the OLE phase, time savings of 8.66, 10.00, and 7.48 months over 14.64, 15.98, and 13.46 months of active treatment on ADCS-ADL, MMSE, and whole-brain atrophy were observed relative to the sham group. DISCUSSION: These findings suggest that further exploration of the effect of evoked gamma oscillations in participants with mild-to-moderate AD, as well as the evaluation of treatment effects using time saved, is merited. HIGHLIGHTS: Evoked gamma oscillation slows functional loss and brain atrophy in Alzheimer\u27s disease.Slowing of functional and cognitive decline and brain atrophy worsening can be expressed as time saved.Evoked gamma oscillation saves 4.83 months of progression in activities of daily living, 4.59 months of progression in Mini-Mental State Examination, and 4.09 months of decline in whole-brain volume over 6 months
Benefits of Maternal Choline Supplementation on Aged Basal Forebrain Cholinergic Neurons (BFCNs) in a Mouse Model of Down Syndrome and Alzheimer\u27s Disease
No full textDown syndrome (DS), stemming from the triplication of human chromosome 21, results in intellectual disability, with early mid-life onset of Alzheimer\u27s disease (AD) pathology. Early interventions to reduce cognitive impairments and neuropathology are lacking. One modality, maternal choline supplementation (MCS), has shown beneficial effects on behavior and gene expression in neurodevelopmental and neurodegenerative disorders, including trisomic mice. Loss of basal forebrain cholinergic neurons (BFCNs) and other DS/AD relevant hallmarks were observed in a well-established trisomic model (Ts65Dn, Ts). MCS attenuates these endophenotypes with beneficial behavioral effects in trisomic offspring. We postulate MCS ameliorates dysregulated cellular mechanisms within vulnerable BFCNs, with attenuation driven by novel gene expression. Here, choline acetyltransferase immunohistochemical labeling identified BFCNs in the medial septal/ventral diagonal band nuclei of the basal forebrain in Ts and normal disomic (2N) offspring at ~11 months of age from dams exposed to MCS or normal choline during the perinatal period. BFCNs (~500 per mouse) were microisolated and processed for RNA-sequencing. Bioinformatic assessment elucidated differentially expressed genes (DEGs) and pathway alterations in the context of genotype (Ts, 2N) and maternal diet (MCS, normal choline). MCS attenuated select dysregulated DEGs and relevant pathways in aged BFCNs. Trisomic MCS-responsive improvements included pathways such as cognitive impairment and nicotinamide adenine dinucleotide signaling, among others, indicative of increased behavioral and bioenergetic fitness. Although MCS does not eliminate the DS/AD phenotype, early choline delivery provides long-lasting benefits to aged trisomic BFCNs, indicating that MCS prolongs neuronal health in the context of DS/AD
Impact of multipoint pelvic fixation and multirod distal constructs on proximal junction biomechanics in cadaveric specimens
No full textOBJECTIVE: Multipoint pelvic fixation with multirod constructs is increasingly used for long-segment deformity constructs to reduce rates of distal failure. However, more robust distal fixation may negatively impact proximal junction biomechanics, and this potential relationship has not been extensively studied. METHODS: Standard nondestructive flexibility tests (7.5 Nm) were performed on 7 cadaveric specimens (L1-pelvis) to assess intervertebral flexibility (range of motion [ROM]), rod strain, and screw bending moments along a posterior fusion construct (pedicle screw and rod [PSR]) spanning L2-S1, supplemented by bilateral primary S2 alar-iliac (S2AI) fixation (2 S2AI screws and 2 rods), followed by additional S2AI screw placement and bilateral accessory rod placement spanning L4-S2AI (4 S2AI screws and 4 rods). Four conditions were tested for each specimen: 1) intact; 2) L2-S1 PSR; 3) L2-S2AI PSR; and 4) L2-S2AI plus L4-S2AI. Data were analyzed using repeated-measures ANOVA. RESULTS: Seven cadaveric specimens were included. Proximal rod strain at the L2-3 level did not change across the varying test conditions in the 7 specimens tested (p \u3e 0.05 for all conditions). There was no significant difference detected in proximal screw strain across conditions (p \u3e 0.05). Finally, no significant difference was found in L2-3 ROM (p \u3e 0.05) across instrumented variations, all of which were more rigid than intact specimens. CONCLUSIONS: Pelvic fixation with 2 or 4 screws and 2 or 4 rods, respectively, did not significantly alter proximal junction screw or rod strain in a cadaveric model. Robust pelvic fixation might protect against distal failure without deleterious effects on the proximal junction