bluuebunny/crossref_metadata_2025 huggingface dataset:
The effectiveness of systemic therapies after surgery for metastatic renal cell carcinoma to the spine: a propensity analysis controlling for sarcopenia, frailty, and nutrition
Authors: Massaad Elie , Saylor Philip J. , Hadzipasic Muhamed , Kiapour Ali , Oh Kevin , Schwab Joseph H. , Schoenfeld Andrew J. , Shankar Ganesh M. , Shin John H.
Published: August 2021

OBJECTIVE

The effectiveness of starting systemic therapies after surgery for spinal metastases from renal cell carcinoma (RCC) has not been evaluated in randomized controlled trials. Agents that target tyrosine kinases, mammalian target of rapamycin signaling, and immune checkpoints are now commonly used. Variables like sarcopenia, nutritional status, and frailty may impact recovery from spine surgery and are considered when evaluating a patient’s candidacy for such treatments. A better understanding of the significance of these variables may help improve patient selection for available treatment options after surgery. The authors used comparative effectiveness methods to study the treatment effect of postoperative systemic therapies (PSTs) on survival.

METHODS

Univariable and multivariable Cox regression analyses were performed to determine factors associated with overall survival (OS) in a retrospective cohort of adult patients who underwent spine surgery for metastatic RCC between 2010 and 2019. Propensity score–matched (PSM) analysis and inverse probability weighting (IPW) were performed to determine the treatment effect of PST on OS. To address confounding and minimize bias in estimations, PSM and IPW were adjusted for covariates, including age, sex, frailty, sarcopenia, nutrition, visceral metastases, International Metastatic RCC Database Consortium (IMDC) risk score, and performance status.

RESULTS

In total, 88 patients (73.9% male; median age 62 years, range 29–84 years) were identified; 49 patients (55.7%) had an intermediate IMDC risk, and 29 (33.0%) had a poor IMDC risk. The median follow-up was 17 months (range 1–104 months) during which 57 patients (64.7%) died. Poor IMDC risk (HR 3.2 [95% CI 1.08–9.3]), baseline performance status (Eastern Cooperative Oncology Group score 3 or 4; HR 2.7 [95% CI 1.5–4.7]), and nutrition (prognostic nutritional index [PNI] first tertile, PNI < 40.74; HR 2.69 [95% CI 1.42–5.1]) were associated with worse OS. Sarcopenia and frailty were not significantly associated with poor survival. PST was associated with prolonged OS, demonstrated by similar effects from multivariable Cox analysis (HR 0.55 [95% CI 0.30–1.00]), PSM (HR 0.53 [95% CI 0.29–0.93]), IPW (HR 0.47 [95% CI 0.24–0.94]), and comparable confidence intervals. The median survival for those receiving PST was 28 (95% CI 19–43) months versus 12 (95% CI 4–37) months for those who only had surgery (log-rank p = 0.027).

CONCLUSIONS

This comparative analysis demonstrated that PST is associated with improved survival in specific cohorts with metastatic spinal RCC after adjusting for frailty, sarcopenia, and malnutrition. The marked differences in survival should be taken into consideration when planning for surgery.
Sex-based differences in outcomes for adult patients presenting to the emergency department with a concussion
Authors: Rowe Brian H. , Yang Esther H. , Gaudet Lindsay A. , Eliyahu Leeor , Junqueira Daniela R. , Beach Jeremy , Mrazik Martin , Cummings Garnet , Voaklander Donald
Published: August 2021

OBJECTIVE

Patients with concussion frequently present to the emergency department (ED). Studies of athletes and children indicate that concussion symptoms are often more severe and prolonged in females compared with males. Given infrequent study of concussion symptoms in the general adult population, the authors conducted a sex-based comparison of patients with concussion.

METHODS

Adults (≥ 17 years of age) presenting with concussion to one of three urban Canadian EDs were recruited. Discharged patients were contacted by telephone 30 and 90 days later to capture the extent of persistent postconcussion symptoms using the Rivermead Post Concussion Symptoms Questionnaire (RPQ). A multivariate logistic regression model for persistent symptoms that included biological sex was developed.

RESULTS

Overall, 250 patients were included; 131 (52%) were women, and the median age of women was significantly higher than that of men (40 vs 32 years). Women had higher RPQ scores at baseline (p < 0.001) and the 30-day follow-up (p = 0.001); this difference resolved by 90 days. The multivariate logistic regression identified that women, patients having a history of sleep disorder, and those presenting to the ED with concussions after a motor vehicle collision were more likely to experience persistent symptoms.

CONCLUSIONS

In a community concussion sample, inconsequential demographic differences existed between adult women and men on ED presentation. Based on self-reported and objective outcomes, work and daily activities may be more affected by concussion and persistent postconcussion symptoms for women than men. Further analysis of these differences is required to identify different treatment options and ensure adequate care and management of injury.
Comparison of 1.0 g/kg of 20% mannitol initiated at different time points and effects on brain relaxation in patients with midline shift undergoing supratentorial tumor resection: a randomized controlled trial
Authors: Zhang Jun-Jie , Liu Yi-Heng , Tu Meng-Yun , Wei Kai , Wang Ying-Wei , Deng Meng
Published: August 2021

OBJECTIVE

Previous studies have suggested the use of 1.0 g/kg of 20% mannitol at the time of skin incision during neurosurgery in order to improve brain relaxation. However, the incidence of brain swelling upon dural opening is still high with this dose. In the present study, the authors sought to determine a better timing for mannitol infusion.

METHODS

One hundred patients with midline shift who were undergoing elective supratentorial tumor resection were randomly assigned to receive early (immediately after anesthesia induction) or routine (at the time of skin incision) administration of 1.0 g/kg body weight of 20% mannitol. The primary outcome was the 4-point brain relaxation score (BRS) immediately after dural opening (1, perfectly relaxed; 2, satisfactorily relaxed; 3, firm brain; and 4, bulging brain). The secondary outcomes included subdural intracranial pressure (ICP) measured immediately before dural opening; serum osmolality and osmole gap (OG) measured immediately before mannitol infusion (T0) and at the time of dural opening (TD); changes in serum electrolytes, lactate, and hemodynamic parameters at T0 and 30, 60, 90, and 120 minutes thereafter; and fluid balance at TD.

RESULTS

The time from the start of mannitol administration to dural opening was significantly longer in the early administration group than in the routine administration group (median 66 [IQR 55–75] vs 40 [IQR 38–45] minutes, p < 0.001). The BRS (score 1/2/3/4, n = 14/26/9/1 vs 3/25/18/4, p = 0.001) was better and the subdural ICP (median 5 [IQR 3–6] vs 7 [IQR 5–10] mm Hg, p < 0.001) was significantly lower in the early administration group than in the routine administration group. Serum osmolality and OG increased significantly at TD compared to levels at T0 in both groups (all p < 0.001). Intergroup comparison showed that serum osmolality and OG at TD were significantly higher in the routine administration group (p < 0.001 and = 0.002, respectively). Patients who had received early administration of mannitol had more urine output (p = 0.001) and less positive fluid balance (p < 0.001) at TD. Hemodynamic parameters, serum lactate concentrations, and incidences of electrolyte disturbances were comparable between the two groups.

CONCLUSIONS

Prolonging the time interval between the start of mannitol infusion and dural incision from approximately 40 to 66 minutes can improve brain relaxation and decrease subdural ICP in elective supratentorial tumor resection.
Neuroanatomical considerations for optimizing thalamic deep brain stimulation in Tourette syndrome
Authors: Morishita Takashi , Sakai Yuki , Iida Hitoshi , Yoshimura Saki , Ishii Atsushi , Fujioka Shinsuke , Tanaka Saori C. , Inoue Tooru
Published: August 2021

OBJECTIVE

Deep brain stimulation (DBS) of the centromedian thalamic nucleus has been reportedly used to treat severe Tourette syndrome, yielding promising outcomes. However, it remains unclear how DBS electrode position and stimulation parameters modulate the specific area and related networks. The authors aimed to evaluate the relationships between the anatomical location of stimulation fields and clinical responses, including therapeutic and side effects.

METHODS

The authors collected data from 8 patients with Tourette syndrome who were treated with DBS. The authors selected the active contact following threshold tests of acute side effects and gradually increased the stimulation intensity within the therapeutic window such that acute and chronic side effects could be avoided at each programming session. The patients were carefully interviewed, and stimulation-induced side effects were recorded. Clinical outcomes were evaluated using the Yale Global Tic Severity Scale, the Yale-Brown Obsessive-Compulsive Scale, and the Hamilton Depression Rating Scale. The DBS lead location was evaluated in the normalized brain space by using a 3D atlas. The volume of tissue activated was determined, and the associated normative connective analyses were performed to link the stimulation field with the therapeutic and side effects.

RESULTS

The mean follow-up period was 10.9 ± 3.9 months. All clinical scales showed significant improvement. Whereas the volume of tissue activated associated with therapeutic effects covers the centromedian and ventrolateral nuclei and showed an association with motor networks, those associated with paresthesia and dizziness were associated with stimulation of the ventralis caudalis and red nucleus, respectively. Depressed mood was associated with the spread of stimulation current to the mediodorsal nucleus and showed an association with limbic networks.

CONCLUSIONS

This study addresses the importance of accurate implantation of DBS electrodes for obtaining standardized clinical outcomes and suggests that meticulous programming with careful monitoring of clinical symptoms may improve outcomes.
Washington Committee for Neurological Surgery: the evolution of neurosurgery’s involvement in public policy
Authors: Stroink Ann R. , Orrico Katie O. , Bean James R.
Published: August 2021

The American Association of Neurological Surgeons/Congress of Neurological Surgeons Washington Committee was formed in 1975 to establish a means for neurosurgery to influence federal health care policy. In response to growing federal health care legislation and regulation, the Washington Committee expanded from its original six members in 1975 to 35 invited liaisons and members by 2020. The Washington Committee, through the Washington Office, expanded political lobbying capacity into numerous important areas of health care policy, including Current Procedural Terminology coding and Medicare reimbursement, Federal Drug Administration (FDA) regulation, healthcare quality oversight, emergency medical services, treatment guidelines, treatment outcome registries, medical liability reform, research funding, and information dissemination. Over 45 yr, the Washington Committee has become an indispensable resource for shaping public policy affecting neurosurgery training, research, and practice.
The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging
Authors: Muscat Stephanie M. , Barrientos Ruth M.
Published: August 2021

Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF, AMPA and NMDA receptor-mediated long-term potentiation.
Physical Computational Complexity and First-order Logic
Authors: Whyman Richard
Published: August 2021

We present the concept of a theory machine, which is an atemporal computational formalism that is deployable within an arbitrary logical system. Theory machines are intended to capture computation on an arbitrary system, both physical and unphysical, including quantum computers, Blum-Shub-Smale machines, and infinite time Turing machines. We demonstrate that for finite problems, the computational power of any device characterisable by a finite first-order theory machine is equivalent to that of a Turing machine. Whereas for infinite problems, their computational power is equivalent to that of a type-2 machine. We then develop a concept of complexity for theory machines, and prove that the class of problems decidable by a finite first order theory machine with polynomial resources is equal to 𝒩𝒫 ∩ co-𝒩𝒫.
On Boolean Automata Networks (de)Composition1
Authors: Perrot Kévin , Perrotin Pacôme , Sené Sylvain
Published: August 2021

Boolean automata networks (BANs) are a generalisation of Boolean cellular automata. In such, any theorem describing the way BANs compute information is a strong tool that can be applied to a wide range of models of computation. In this paper we explore a way of working with BANs which involves adding external inputs to the base model (via modules), and more importantly, a way to link networks together using the above mentioned inputs (via wirings). Our aim is to develop a powerful formalism for BAN (de)composition. We formulate three results: the first one shows that our modules/wirings definition is complete; the second one uses modules/wirings to prove simulation results amongst BANs; the final one expresses the complexity of the relation between modularity and the dynamics of modules.
Circular Interval-valued Computers and Simulation of (Red-green) Turing Machines
Authors: Nagy Benedek , Vályi Sándor
Published: August 2021

Interval-valued computing is a kind of massively parallel computing. It operates on specific subsets of the interval [0,1) – unions of subintervals. They serve as basic data units and are called interval-values. It was established in [9], by a rather simple observation, that interval-valued computing, as a digital computing model, has computing power equivalent to Turing machines. However, this equivalence involves an unlimited number of interval-valued variables. In [14], the equivalence with Turing machines is established using a simulation that uses only a fixed number of interval-valued variables and this number depends only on the number of states of the Turing machine – in a logarithmic way. The simulation given there allows us to extend interval-valued computations into infinite length to capture the computing power of red-green Turing machines. In this extension of [14], based on the quasi-periodic techniques used in the simulations in that paper, a reformulation of the interval-valued computations is given, named circular interval-valued computers. This reformulation enforces the finiteness of the number of used interval-valued variables by building the finiteness into the syntax rules.
The impact of internal factors on the use of technology in higher education in Saudi Arabia during the COVID-19 pandemic
Authors: Al-Ghurbani Abdullah Mohammed , Jazim Fawaz , Abdulrab Mohammed , Al-Mamary Yaser Hasan S. , Khan Imran
Published: August 2021

BACKGROUND: Technology has recently become a major component of the educational field and learning process for it provides students with opportunities to learn more effectively and to operate efficiently in this age of technological advances. As academics, the use of technology in universities is transforming our work, and more specifically the way we support students in the classroom. As higher education institutions bring more technology into their classrooms, academics will in turn strive to put more technology in their students’ hands. That is, if they are prepared to do so. More importantly, ICT (Information and Communication Technology) in this ongoing COVID-19 pandemic becomes a central and integral focus globally regardless one is associated with college or university. OBJECTIVE: This paper therefore attempts to examine the internal factors that should be taken into consideration when using technology for teaching and learning purposes in higher education in Saudi Arabia. METHODS: The study develops a number of hypotheses and a theoretical framework based on a questionnaire conducted among the faculty staff in Hail university to test the study hypotheses. RESULTS: All the study six hypotheses have been supported. The relationship among these hypotheses are clear and significant. Data analysis of this study have shown that perceived usefulness, perceived ease of use, computer self-efficacy, attitudes and computer anxiety have direct and substantial effect on the university teaching staff’s intention to use technology. CONCLUSIONS: The findings of this study will for sure assist in overcoming the problems and difficulties facing the use of ICT in higher education in Saudi Arabia, particularly those challenges which have arisen amid the outbreak of the COVID-19 pandemic.
A Comparison of Cross-Sectional and Longitudinal Methods of Defining Objective Subtle Cognitive Decline in Preclinical Alzheimer’s Disease Based on Cogstate One Card Learning Accuracy Performance
Authors: Pudumjee Shehroo B. , Lundt Emily S. , Albertson Sabrina M. , Machulda Mary M. , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Petersen Ronald C. , Mielke Michelle M. , Stricker Nikki H.
Published: August 2021

Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer’s disease continuum. Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (ΔOBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer’s disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance. Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50 + with amyloid and tau PET scans (n = 311) comprised the biomarker-defined sample. A case-control sample of participants aged 65 + remaining cognitively unimpaired for at least 30 months included 64 who subsequently developed MCI (incident MCI cases) and 184 controls, risk-set matched by age, sex, education, and visit number. sOBJ was assessed by OCL z-scores. ΔOBJ was assessed using within subjects’ standard deviation and annualized change from linear regression or linear mixed effects (LME) models. Concordance measures Area Under the ROC Curve (AUC) or C-statistic and odds ratios (OR) from conditional logistic regression models were derived. sOBJ and ΔOBJ were modeled jointly to compare methods. Results: sOBJ and ΔOBJ-LME methods differentiated A+T+ from A-T- (AUC = 0.64, 0.69) and controls from incident MCI (C-statistic = 0.59, 0.69) better than chance; other ΔOBJ methods did not. ΔOBJ-LME improved prediction of future MCI over baseline sOBJ (p = 0.003) but not over 30-month sOBJ (p = 0.09). Conclusion: Longitudinal decline did not offer substantial benefit over cross-sectional assessment in detecting preclinical Alzheimer’s disease or incident MCI.
A GLP-1/GIP Dual Receptor Agonist DA4-JC Effectively Attenuates Cognitive Impairment and Pathology in the APP/PS1/Tau Model of Alzheimer’s Disease1
Authors: Cai Hong-Yan , Yang Dan , Qiao Jing , Yang Jun-Ting , Wang Zhao-Jun , Wu Mei-Na , Qi Jin-Shun , Hölscher Christian
Published: August 2021

Background: Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the Golgi method, and biochemical analysis of biomarkers. Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion: DA4-JC is a promising drug for the treatment of AD.
Novel Plasma miRNAs as Biomarkers and Therapeutic Targets of Alzheimer’s Disease at the Prodromal Stage
Authors: He Haining , Liu An , Zhang Wei , Yang Huanqing , Zhang Minmin , Xu Hua , Liu Yuanyuan , Hong Bo , Yan Feng , Yue Ling , Wang Jinghua , Xiao Shifu , Xie Zuoquan , Wang Tao
Published: August 2021

Background: Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD) involving imbalanced beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). MicroRNAs (miRNAs) are associated with AD. Objective: This study aimed to investigated whether plasma miRNAs can predict prodromal AD or are associated with AD pathology. Methods: Participants in the discovery set (n = 10), analysis set (n = 30), and validation set (n = 80) were screened from the China Longitudinal Aging Study. RNA was extracted from the participants’ plasma. Microarray sequencing provided miRNA profiles and differentially expressed miRNAs (DEmiRNAs) in the discovery set included patients with 18F-Flutemetamol positron emission tomography scan-confirmed aMCI. Potential biomarkers were screened in the analysis set. The predict capability of candidate miRNAs was assessed in the validation set. Candidate miRNAs modulation of BACE1 expression was explored in rat and human hippocampal neurons in vitro. Results: We verified 46 significant DEmiRNAs between the aMCI and NC groups (p < 0.05), among which 33 were downregulated. In the analysis set, miR-1185-2-3p, miR-1909-3p, miR-22-5p, and miR-134-3p levels decreased significantly in the aMCI group. These miRNAs and previously identified miR-107 were selected as potential biomarkers. A prediction model comprising these five miRNAs showed outstanding accuracy (81.25%) to discriminate aMCI at cut-off value of 0.174. Except for miR-134-3p, the other four miRNAs significantly suppressed Bace1 expression in rat hippocampal neurons in vitro. BACE1 modulation of miR-1185-2-3p, miR-1909-3p, and miR-134-3p was confirmed in human hippocampal neurons in vitro. Conclusion: A predictive model consisting of five BACE1-related plasma miRNAs could be a novel biomarker for aMCI.
Retinal Amyloid Imaging for Screening Alzheimer’s Disease
Authors: Tadokoro Koh , Yamashita Toru , Kimura Shuhei , Nomura Emi , Ohta Yasuyuki , Omote Yoshio , Takemoto Mami , Hishikawa Nozomi , Morihara Ryuta , Morizane Yuki , Abe Koji
Published: August 2021

Background: Cost-effective and noninvasive methods for in vivo imaging of amyloid deposition are needed to screen Alzheimer’s disease (AD). Although retinal amyloid is a possible diagnostic marker of AD, there are very few studies on in vivo retinal amyloid imaging. Objective: To examine the usefulness of in vivo imaging of retinal amyloid in AD patients. Methods: To examine amyloid deposition, 30 Japanese subjects (10 normal control (NC), 7 with mild cognitive impairment (MCI), and 13 with AD) underwent a complete ophthalmic examination, including fundus imaging by scanning laser ophthalmoscopy before and after oral curcumin intake. Results: Retinal amyloid deposition was greater in AD than in NC subjects (*p < 0.05) while MCI showed a slight but insignificant increase of retinal amyloid deposition relative to NC subjects. Retinal amyloid deposition was correlated with whole gray matter atrophy (r = 0.51, *p < 0.05) but not with the cognitive score of the Mini-Mental State Examination, nor with medial temporal lobe atrophy. Conclusion: The present noninvasive in vivo detection of retinal amyloid deposition is useful for screening AD patients.
Association of Amyloid-β Pathology with Decision Making and Scam Susceptibility
Authors: Kapasi Alifiya , Yu Lei , Stewart Christopher , Schneider Julie A. , Bennett David A. , Boyle Patricia A.
Published: August 2021

Background: Recent findings suggest that poor decision making and increased scam susceptibility are harbingers of Alzheimer’s disease (AD) dementia and may be among the earliest behavioral manifestations of pathologic cognitive aging. However, the degree to which poor decision making and scam susceptibility reflect accumulating Alzheimer’s disease (AD) pathology remains unclear. Objective: To investigate the associations of AD pathology with decision making and scam susceptibility in older adults without dementia. Methods: Data came from 198 deceased participants without clinical dementia (mean age at death = 90 years; 69%women) from two ongoing studies of aging. All underwent annual clinical evaluations, completed assessments of healthcare and financial decision making and scam susceptibility, and brain donation. Neuropathologic evaluations quantified pathologic hallmarks of AD, amyloid-β and tau-tangles, Lewy body pathology, and TDP-43 proteinopathy. Results: In linear regression models adjusted for demographics, amyloid-β pathology was associated with lower decision making (estimate = –0.35; SE = 0.16, p = 0.03), particularly healthcare decision making (estimate = –0.20; SE = 0.09, p = 0.03), as well as greater scam susceptibility (estimate = 0.12; SE = 0.04, p = 0.003); tau-tangle pathology was not related. Further, TDP-43 pathology was associated with greater scam susceptibility (estimate = 0.10; SE = 0.04; p = 0.02). Conclusion: Accumulating AD pathology, particularly amyloid-β, is associated with poor decision making and increased scam susceptibility among older persons without overt cognitive impairment. These findings provide compelling evidence that decision making and scam susceptibility are sensitive to the earliest pathological changes of AD.
Gut Microbiota and Alzheimer’s Disease: Pathophysiology and Therapeutic Perspectives
Authors: Li Yanli , Wang Rui , Li Qian , Wang Yan-Jiang , Guo Junhong
Published: August 2021

Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.
De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer’s Disease Associated with Spasticity: A Case Report
Authors: Agüero Pablo , Sainz María José , Téllez Raquel , Lorda Isabel , Ávila Almudena , García-Ribas Guillermo , Rodríguez Patricia Paredes , Gómez-Tortosa Estrella
Published: August 2021

We report a patient with sporadic Alzheimer’s disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aβ42 level and Aβ42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-β neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.
Implication of Small Vessel Disease MRI Markers in Alzheimer’s Disease and Lewy Body Disease1
Authors: Park Mincheol , Baik Kyoungwon , Lee Young-gun , Kang Sung Woo , Jung Jin Ho , Jeong Seong Ho , Lee Phil Hyu , Sohn Young H. , Ye Byoung Seok
Published: August 2021

Background: Small vessel disease (SVD) magnetic resonance imaging (MRI) markers including deep and periventricular white matter hyperintensities (PWMH), lacunes, and microbleeds are frequently observed in Alzheimer’s disease (AD) and Lewy body disease (LBD), but their implication has not been clearly elucidated. Objective: To investigate the implication of SVD MRI markers in cognitively impaired patients with AD and/or LBD. Methods: We consecutively recruited 57 patients with pure AD-related cognitive impairment (ADCI), 49 with pure LBD-related cognitive impairment (LBCI), 45 with mixed ADCI/LBCI, and 34 controls. All participants underwent neuropsychological tests, brain MRI, and amyloid positron emission tomography. SVD MRI markers including the severity of deep and PWMH and the number of lacunes and microbleeds were visually rated. The relationships among vascular risk factors, SVD MRI markers, ADCI, LBCI, and cognitive scores were investigated after controlling for appropriate covariates. Results: LBCI was associated with more severe PWMH, which was conversely associated with an increased risk of LBCI independently of vascular risk factors and ADCI. PWMH was associated with attention and visuospatial dysfunction independently of vascular risk factors, ADCI, and LBCI. Both ADCI and LBCI were associated with more lobar microbleeds, but not with deep microbleeds. Conclusion: Our findings suggest that PWMH could reflect degenerative process related with LBD, and both AD and LBD independently increase lobar microbleeds.
Fine or Gross Motor Index as a Simple Tool for Predicting Cognitive Impairment in Elderly People: Findings from The Irish Longitudinal Study on Ageing (TILDA)
Authors: Liu Xiao , Abudukeremu Ayiguli , Jiang Yuan , Cao Zhengyu , Wu Maoxiong , Sun Runlu , Chen Zhiteng , Chen Yangxin , Zhang Yuling , Wang Jingfeng
Published: August 2021

Background: Several kinds of motor dysfunction can predict future cognitive impairment in elderly individuals. However, the ability of the fine motor index (FINEA) and gross motor index (GROSSA) to predict the risk of cognitive impairment has not been assessed. Objective: We investigated the associations between FINEA/GROSSA and cognitive impairment. Methods: The data of 4,745 participants from The Irish Longitudinal Study on Ageing (TILDA) were analyzed. Cognitive function was assessed using the Mini-Mental State Examination (MMSE). We first assessed the correlation between the FINEA/GROSSA and MMSE in a cross-sectional study. Then, we further investigated the predictive role of the incidence of cognitive impairment in a prospective cohort study. Results: We found that both FINEA and GROSSA were negatively correlated with MMSE in both the unadjusted (FINEA: B = –1.00, 95%confidence intervals (CI): –1.17, –0.83, t = –11.53, p < 0.001; GROSSA: B = –0.85, 95%CI: –0.94, –0.76, t = –18.29, p < 0.001) and adjusted (FINEA: B = –0.63, 95%CI: –0.79, –0.47, t = –7.77, p < 0.001; GROSSA: B = –0.57, 95%CI: –0.66, –0.48, t = –12.61, p < 0.001) analyses in a cross-sectional study. In a prospective cohort study, both high FINEA and high GROSSA were associated with an increased incidence of cognitive function impairment (FINEA: adjusted odds ratios (OR) = 2.35, 95%CI: 1.05, 5.23, p = 0.036; GROSSA adjusted OR = 3.00, 95%CI: 1.49, 6.03, p = 0.002) after 2 years of follow-up. Conclusion: Higher FINEA and GROSSA scores were both associated with an increased incidence of cognitive impairment. FINEA or GROSSA might be a simple tool for identifying patients with cognitive impairment.
A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons
Authors: Yu Yang , Gao Yang , Winblad Bengt , Tjernberg Lars O. , Schedin-Weiss Sophia
Published: August 2021

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.
A speed inference planning of groove cutting robot based on machine vision and improved fuzzy neural network
Authors: Xuejian Zhang , Xiaobing Hu , Hang Li
Published: August 2021

To ensure the cutting speed during the cutting operation, this paper proposes a groove cutting speed inference planning system that relies on production experience and set parameters and is based on machine vision and a two-level fuzzy neural hybrid network. The overall structure of the inference system is designed, including the mechanical body, vision system, and fuzzy neural hybrid network. The contour information of the part is obtained using industrial cameras and digital image processing systems. The cutting speed of the trajectory segment is inferred based on the related processing parameters and the secondary fuzzy neural hybrid network. Finally, all of the processing parameters are transmitted to the PLC, so that the robot can work according to the predetermined displacement and speed. Simulations verify that the speed inference planning system offers certain advantages compared to the traditional one. The appearance of the speed inference planning realises independent design and planning of the cutting speed, and further ensures the unity of the cutting quality and cutting speed. This proposed method provides a new direction for the development and transformation of machining processes that rely on manual experience and in which expert systems cannot be used.
Self-Perception of Voice and Swallowing Handicap in Parkinson’s Disease
Authors: Silbergleit Alice K. , Schultz Lonni , Hamilton Kendra , LeWitt Peter A. , Sidiropoulos Christos
Published: August 2021

Background: Hypokinetic dysarthria and dysphagia are known features of Parkinson’s disease; however, self-perception of their handicapping effects on emotional, physical, and functional aspects of quality of life over disease duration is less understood. Objective: 1) Based upon patient self-perception, to determine the relationship of the handicapping effects of dysphagia and dysphonia with time since diagnosis in individuals with Parkinson’s disease; 2)To determine if there is a relationship between voice and swallowing handicap throughout the course of Parkinson’s disease. Method: 277 subjects completed the Dysphagia Handicap Index and the Voice Handicap Index. Subjects were divided into three groups based on disease duration: 0–4 years, 5–9 years, and 10 + years. Results: Subjects in the longer duration group identified significantly greater perceptions of voice and swallowing handicap compared to the shorter duration groups. There was a significant positive correlation between the DHI and VHI. Conclusion: Self-perception of swallowing and voice handicap in Parkinson’s disease are associated with later stages of disease and progress in a linear fashion. Self-perception of voice and swallowing handicap parallel each other throughout disease progression in Parkinson’s disease. Individuals may be able to compensate for changes in voice and swallowing early while sensory perceptual feedback is intact. Results support early targeted questioning of patient self-perception of voice and swallowing handicap as identification of one problem indicates awareness of the other, thus creating an opportunity for early treatment and maintenance of swallowing and communication quality of life for as long as possible.
Improved Delivery Methods for Gene Therapy and Cell Transplantation in Parkinson’s Disease
Authors: Larson Paul S.
Published: August 2021

A number of cell transplantation and gene therapy trials have been performed over the last three decades in an effort to restore function in Parkinson’s disease. Much has been learned about optimizing delivery methods for these therapeutics. This is particularly true in gene therapy, which has predominated the clinical trial landscape in recent years; however, cell transplantation for Parkinson’s disease is currently undergoing a renaissance. Innovations such as cannula design, iMRI-guided surgery and an evolution in delivery strategy has radically changed the way investigators approach clinical trial design. Future therapeutic strategies may employ newer delivery methods such as chronically implanted infusion devices and focal opening of the blood brain barrier with focused ultrasound.
Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion
Authors: Rosebraugh Matthew , Liu Wei , Neenan Melina , Facheris Maurizio F.
Published: August 2021

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.
Development and persistence of patient-reported visual problems associated with serotonin reuptake inhibiting antidepressants
Authors: Healy David , Mangin Dee , Lochhead Jonathan
Published: August 2021

BACKGROUND: The majority of antidepressants inhibit serotonin reuptake and include the selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the serotonin reuptake inhibiting tricyclic antidepressants. OBJECTIVE: The objective of this study was to investigate and describe the range and impact of reported adverse visual effects linked to serotonin reuptake inhibiting antidepressants. METHODS: Using data from a global database of patient spontaneous reports of drug adverse events, we systematically identified eligible reports of visual problems linked to the use of serotonin reuptake inhibiting antidepressants. We analyzed these data using simple descriptive statistics to present the range and impact. RESULTS: We identified 124 reports of visual problems. Reports originate from 18 countries and involve 11 different drugs. The most commonly reported symptoms were vision blurred/visual acuity reduced (n = 79, 63.7%), night blindness (n = 22, 17.7%), vitreous floaters (n = 21, 16.9%), photophobia (n = 19, 15.3%), diplopia (n = 15, 12.1%), palinopsia (n = 13, 10.5%), visual field defect (n = 12, 9.7%), photopsia (n = 11, 8.9%) and visual snow syndrome (n = 11, 8.9%). 74 patients indicated that the side effect was bad enough to affect everyday activities, 62 had sought health care, and 50 indicated that their work had been affected. 49 patients reported an enduring vision problem after discontinuation of treatment. CONCLUSIONS: The data suggest that serotonin reuptake inhibiting antidepressants can produce a range of adverse effects on vision that in some cases can be long-lasting after discontinuation of the drug. Further efforts are needed to understand the mechanisms involved, the incidence among those prescribed these medications, and identify any risk or mitigation factors.
An iterative reconstruction method for sparse-projection data for low-dose CT
Authors: Huang Ying , Wan Qian , Chen Zixiang , Hu Zhanli , Cheng Guanxun , Qi Yulong
Published: August 2021

Reducing X-ray radiation is beneficial for reducing the risk of cancer in patients. There are two main approaches for achieving this goal namely, one is to reduce the X-ray current, and another is to apply sparse-view protocols to do image scanning and projections. However, these techniques usually lead to degradation of the reconstructed image quality, resulting in excessive noise and severe edge artifacts, which seriously affect the diagnosis result. In order to overcome such limitation, this study proposes and tests an algorithm based on guided kernel filtering. The algorithm combines the characteristics of anisotropic edges between adjacent image voxels, expresses the relevant weights with an exponential function, and adjusts the weights adaptively through local gray gradients to better preserve the image structure while suppressing noise information. Experiments show that the proposed method can effectively suppress noise and preserve the image structure. Comparing with similar algorithms, the proposed algorithm greatly improves the peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and root mean square error (RMSE) of the reconstructed image. The proposed algorithm has the best effect in quantitative analysis, which verifies the effectiveness of the proposed method and good image reconstruction performance. Overall, this study demonstrates that the proposed method can reduce the number of projections required for repeated CT scans and has potential for medical applications in reducing radiation doses.