bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of fall risk and associated factors in patients with dementia
Authors: Kilicaslan Kimya , Tulek Zeliha , Gurvit Hakan , Bilgiç Başar , Hanagasi Hasmet
Published: June 2023

Background

Falling, which is common in the elderly and leads to negative consequences, can also be seen in dementia patients. The aim of this study is to determine the risk of falls in patients with dementia and to evaluate the factors associated with falls.

Method

The sample of this cross‐sectional study consisted of 95 patients with a diagnosis of definite dementia who attended a dementia outpatient clinic in a university hospital in Istanbul between January and March 2020. Patients using assistive devices while walking were not included in the study. A sociodemographic form, DENN Fall Risk Assessment Scale, Mini Mental State Test (MMSE), Neuropsychiatric Inventory (NPI), Apathy Assessment Scale (AES), Clinical Dementia Rating Scale (CDR), Cornell Depression in Dementia Scale (CSDD), Lawton and Brody Instrumental Activities of Daily Living (Lawton IADL), and Katz Activities of Daily Living (Katz ADL) Scale were used for data collection.

Results

It was determined that 53.7% of the patients were female and the mean age was 73.1±11.4. Most of the patients (64.2%) had Alzheimer’s type dementia, 49.5% had mild or moderate dementia, 75.8% had an additional chronic disease, 22.1% were semi‐dependent in movement activity. 47.4% of the individuals had a history of fall in the last month, 48.9% had fallen at least 2 times, the average number of falls was 1.5±0.5, 70.5% of the patients had injuries after falling, and the mean DENN Fall Risk score was found to be 10.4±3.4. In the group with a history of falling non‐Alzheimer dementias were more common (p = 0.018), NPI symptom (p<0.001) and bother (p<0.001) scores were higher, Lawton IADL scores were lower (p = 0.009), AES clinician (p = 0.054) and caregiver (p = 0.052) scores and Cornell depression score (CSDD) (p = 0.005) were higher.

Conclusion

Falling, which is the most common geriatric syndrome in dementia patients, can lead to negative patient outcomes. Most dementia patients have a history of falling and post‐fall injury. Factors associated with falls in dementia patients should be known, and appropriate nursing interventions should be made to prevent falls by recognizing the risk of falling. More work is needed on this subject.
Yoga prevents grey matter volume decline in women at risk for Alzheimer’s Disease: A randomized controlled trial
Authors: Lavretsky Helen
Published: June 2023

Background

Female sex, subjective cognitive decline (SCD), and cardiovascular risk factors (CVRF) are known risk factors for developing Alzheimer’s disease (AD). We previously demonstrated that yoga improved depression, resilience, memory and executive functions, increased hippocampal choline concentrations and modulated brain connectivity in older adults with mild cognitive impairment. In this study (NCT03503669), we investigated brain gray matter volume (GMV) changes in older women with SCD and CVRF following three months of yoga compared to memory training (MET).

Methods

Eleven women (mean age = 61.45, SD = 6.58) with CVRF and SCD completed twelve weeks of Kundalini yoga (KY) and Kirtan Kriya (KK), while eleven women (mean age = 64.55, SD = 6.41) underwent MET. T1‐weighted MRI scans were acquired at baseline and follow‐up using a Siemens 3T Prisma scanner. We used Freesurfer 6 and longitudinal two‐step models to test group differences in symmetrized percent change in GMV. Resulting clusters were corrected and Monte‐Carlo simulations applied at an alpha level of 0.05. Region‐of‐interest analysis was performed for hippocampus and amygdala.

Results

Compared to KY+KK, MET showed reductions in GMV in left prefrontal, pre‐ and post‐central, supramarginal, superior temporal and pericalcarine cortices, right paracentral, postcentral, superior and inferior parietal cortices, the banks of the superior temporal sulcus, and the pars opercularis. Right hippocampal volume increased after yoga but did not survive corrections.

Conclusion

Yoga training may offer neuroprotective effects compared to MET in preventing neurodegenerative changes and cognitive decline, even over short time intervals. Future analyses will address changes in functional connectivity in both groups.
Multimodal, longitudinal digital brain health platform using participant‐driven study design
Authors: Popp Zachary T , Low Spencer , Kolachalama Vijaya B. , Lin Honghuang , Rahman Md Salman , Prabhu Meha , Chan Cameron , Salgado Maria , Au Rhoda
Published: June 2023

Background

Longitudinal studies that embrace digital data collection offer a low cost, time‐efficient solution compared to traditional methods. As such, ongoing advances in data science combined with the wealth of data produced by digital technologies can enable a pragmatic shift from investigator‐ to participant‐driven protocols. A participant‐driven study design might bring major efficiencies across the life course of longitudinal studies.

Method

We recruited participants from the Boston University Alzheimer’s Disease Research Center to a longitudinal study on brain health utilizing a multimodal, technology‐based protocol. Remote assessment technologies included active and passive engagement mobile and computer‐based applications and wearable devices to capture digital measures of cognition, voice, gait, motor activity, and activities of daily living. A full list of study technologies is shown in Table 1. Participants specify which technologies they would like to continue to use, providing a sense of ownership that promotes study participation.

Result

Through January 2022, a total of 22 participants (average age = 74.3+ 8.8 years; 68.2% women) have been recruited. The majority of participants (n = 21, 95.5%) have expressed a willingness to engage with multiple technologies. Among those enrolled for >3 months, 14 participants (87.5%) have opted to use 3 or more technologies (mean number of technologies = 4.38). Several technologies only worked on specific operating systems (NeuraMetrix, Longevity). Compatibility (n = 16, 72.7%) was the most frequent factor in leading a participant to not use a study technology, followed by concern over the burden of using an additional device or application (n = 14, 63.6%). The most common factor leading participants to select a given technology was the availability of participant‐facing data (n = 15, 68.2%), such as step counts or scores on gamified cognitive tests.

Conclusion

Through the use of a participant‐driven study design, we have been able to conduct longitudinal brain health digital phenotyping with high uptake of digital technologies. Participant’s selections offer insights to investigators assessing which technologies to use in clinical research. Digital data collection opens opportunities for participant‐driven approaches that can enable longitudinal follow‐up with broader more inclusive reach with appropriate retention of data quality.
Design, docking, synthesis and biological evaluation of chromone derivatives as dual inhibitors of Interleukin‐6 and acetylcholinesterase for treatment of Alzheimer’s Disease
Authors: Kaur Sukhvir , Bansal Yogita , Mishra Shivam
Published: June 2023

Background

Interleukin‐6 (IL‐6) and acetylcholinesterase (AChE) are two important targets implicated in the progression of Alzheimer’s Disease (AD). Concurrent inhibition of both IL‐6 and AChE by a molecule presents an effective strategy for the treatment of AD. In the present study, novel molecules are designed by coupling a chromone and a N,N‐disubstituted carbamoyl amine as pharmacophore for IL‐6 and AChE inhibition, respectively.

Method

Four series (S1‐S4) of 40 compounds are designed by coupling the two selected pharmacophore through alkyl linkers of different lengths (1‐4 carbon atoms). All designed compounds are docked in AChE (PDB 1EVE). The compounds having docking score ±20% of donepezil (the lead molecule) are synthesised, and evaluated for AChE inhibitory activity. The compounds showing >45% inhibition of AChE are further evaluated for IL‐6 inhibitory activity.

Result

Twelve best‐fit compounds (AChE docking score >8.3) among all designed compounds are selected for synthesis. The data suggests that a 1‐ or 2‐carbon atom(s) linker is conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 12 selected compounds suggest that these can cross the blood brain barrier with good oral bioavailability. These compounds are synthesised and evaluated for anti‐AChE activity. Five compounds, showing >45% inhibition of AChE, are further evaluated for IL‐6 inhibitory activity. Compound S1f is found to be the most potent inhibitor of both AChE and IL‐6 (IC50 0.7 and 0.8 µM, respectively).

Conclusion

A chromone moiety connected to a piperidine ring through a 1‐carbon atom linker may prove as a useful template for the development of new chemical entities effective against AD.
Vitamin D intake and cognitive decline in African Americans and European Americans: The role of diet and supplements
Authors: Dhana Klodian , Barnes Lisa L. , Agarwal Puja , Liu Xiaoran , Dhana Anisa , Desai Pankaja , Aggarwal Neelum T. , Evans Denis A , Rajan Kumar B
Published: June 2023

Background

Vitamin D intake and supplementation has received considerable interest in dementia research because the prevalence of vitamin D deficiency is higher among older adults, particularly among older African Americans and cognitively impaired individuals. We prospectively examined the role of vitamin D intake, from both diet and supplements, in association with cognitive decline in African Americans and European Americans.

Method

Utilizing data from the population‐based Chicago Health and Aging Project, we studied 2,061 African Americans and 1,329 European Americans with dietary vitamin D data and cognitive testing over 18 years of follow‐up. Multivariable linear mixed‐effects models adjusted for age, sex, education, APOE e4, body mass index, late‐life cognitive activities, physical activity, comorbidities, total energy intake, and their respective interactions with follow‐up time were used to determine the association of vitamin D intake with cognitive decline.

Result

On average, the vitamin D intake was lower in African Americans than European Americans (210.2 IU/d vs. 348.7 IU/d). In African Americans, participants in the highest tertile had a slower cognitive decline of 0.019 units/year (95%CI 0.009, 0.030) compared to those in the lowest tertile of dietary intake. The use of vitamin D supplementation was not associated with cognitive decline in African Americans (β 0.004, 95%CI ‐0.006, 0.013). In European Americans, vitamin D intake was not associated with cognitive decline.

Conclusion

Dietary vitamin D may help slow the rate of cognitive decline in African Americans as they age.
Longitudinal association between exposure to vitamin D supplementation and incident dementia – A study of dementia‐free older adults
Authors: Ghahremani Maryam , Chen Hung‐Yu , Creese Byron , Goodarzi Zahra , Smith Eric E. , Ismail Zahinoor
Published: June 2023

Background

In the absence of clear disease‐modifying drugs for dementia, modifiable risk factors have been explored to slow disease progression. Vitamin D deficiency is a risk factor, associated with higher risk of dementia. However, the role of vitamin D supplementation has been a subject of debate. Here we explored longitudinal associations between vitamin D supplementation and incident dementia in dementia‐free older adults from the National Alzheimer’s Coordinating Center (NACC).

Method

All participants had normal cognition (NC) or mild cognitive impairment (MCI) at baseline. Exposure to vitamin D supplementation was based on the NACC A4 medication form. Three vitamin D formulations were considered: calcium‐vitamin D, cholecalciferol, and ergocalciferol. For the primary analysis, participants with baseline exposure to any supplement were considered D+, while those without any exposure in advance of dementia diagnosis were considered D‐. Kaplan‐Meier curves were generated to compare ten‐year dementia‐free survival between D+ and D‐ groups. Cox proportional hazards models were implemented to assess the risk of dementia across vitamin D exposure groups, adjusted for baseline age, sex, years of education, race, APOE‐e4 status, cognitive diagnosis, and depression. To distinguish the associations of various vitamin D formulations with risk of dementia, sensitivity analyses were conducted to independently examine the effect of each formulation (calcium‐vitamin D, cholecalciferol, ergocalciferol).

Result

The final sample consisted of 2836 D+ (mean age = 72.1; 68.4% female) and 5075 D‐ participants (mean age = 72; 45.1% female). MCI was more prevalent in D‐ vs D+ participants (35.7% vs 26.8%; p<0.001). Similarly, depression was more prevalent in D‐ vs D+ participants (6.9% vs. 4.3%, p<0.001). Across all three vitamin D formulations, exposure was associated with longer dementia‐free survival (p<0.001) and lower adjusted hazard ratio (HR) for incident dementia compared to no exposure (calcium‐vitamin D: HR = 0.56, 95%CI: 0.47‐0.67, p<0.001; cholecalciferol: HR = 0.72, 95%CI: 0.56‐0.91, p = 0.007; ergocalciferol: HR = 0.75, 95%CI: 0.63‐0.89, p<0.001)

Conclusion

Our findings demonstrate that while adjusting for demographic, cognitive, behavioral, and genetic factors, exposure to vitamin D supplementation (calcium‐vitamin D, cholecalciferol, or ergocalciferol) in dementia‐free older adults was associated with lower risk of dementia, implicating vitamin D as a potential agent for dementia prevention.
Histopathologic brain age estimation via context‐aware attention‐based deep multiple instance learning
Authors: Marx Gabriel A.
Published: June 2023

Background

While a large list of age‐related changes have been described in the human brain, the extent to which they represent the result of common pathological reactions versus signatures of underlying brain aging remains unclear. One approach to sorting out the relative importance of the myriad of changes is deep learning, which has emerged as a powerful tool for image analysis and computer vision. However, large digitized whole slide image datasets from human aging brains have not been previously available.

Method

In this study, we leveraged a large novel collection of uniformly processed digitized human post‐mortem brain tissue sections to create a histological brain age estimation model. We further investigated the effect of cognitive impairment and exogenous stress on the model. This was accomplished by developing a context‐aware attention‐based deep multiple instance learning model on 702 human brain tissues sections (age range 50‐110 yr) from the hippocampus stained with Luxol Fast Blue counterstained with hematoxylin and eosin (LH&E) on a brain age estimation task.

Result

Our model estimated brain age within a mean absolute error of 6.2 years. Learned attention weights corresponded to neuroanatomical regions known to be vulnerable to age‐related change. We found that deviations from our estimated histopathologic brain age significantly correlated with the clinical marker of cognitive status (p = 0.042). In addition, we found evidence of significantly accelerated age (p = 1.12×10‐23) in a cohort of subjects with a neuropathological diagnosis of chronic traumatic encephalopathy (CTE), a neurodegenerative disease caused by mild yet repetitive traumatic brain injury, that displays features that overlap with aging.

Conclusion

These data indicate that estimated histopathologic age can be used as a reliable pathologic correlate to identify factors that contribute to accelerated or decelerated brain aging.
Quantifying three types of abnormal language in semantic variant primary progressive aphasia
Authors: Jones Amelia , Hochberg Daisy , Quimby Megan , Dickerson Bradford C.
Published: June 2023

Background

Patients with the semantic variant of Primary Progressive Aphasia (svPPA) experience a gradual loss of semantic memory, impairing word retrieval and word comprehension. As such, svPPA patients often use superordinate, vague, and empty words. These patients often use language that refers to one’s own experience (“self‐referential”), one’s language impairments (“inability”), and/or contains tangents (“tangential”). These forms of aberrant language were identified previously as distinguishing svPPA from the other canonical variants of PPA (Gallee et al., 2021).

Method

Speech samples of the WAB picnic scene from 15 svPPA patients were analyzed by counting words and categorizing three forms of aberrant language at two timepoints (30 samples total), baseline and follow‐up (at least 12 months post baseline). Words were identified as self‐referential, inability, or tangential. Quantitative analyses were conducted to look for relationships between total word count and each of the three forms of aberrant language.

Result

Preliminary results showed a strong correlation (r = .97) between the total number of aberrant words and the total number of words in the picture description transcriptions. At T1, 40% (6/15) used self‐referential words, 87% (13/15) used inability words, and 53% (8/15) used tangential words. At T2, 67% (10/15) used self‐referential words, 100% (15/15) used inability words, and 67% (10/15) used tangential words. Inability is the most prominent type of aberrant language. Longitudinal analyses are ongoing to investigate consistency or inconsistency within patients and relationship to aphasia severity.

Conclusion

Preliminary findings suggest patients with svPPA produce distinct types of aberrant language in a picture description task. The prominent use of inability words may be due to its scripted nature in that svPPA patients use these phrases repeatedly and may be related to disinhibition. Further, it is notable that several components of language not analyzed in this study, including grammar, syntax, and content units, are potentially informative. Using this method provides an efficient way to characterize speech of svPPA patients, which may lead to early subtyping, prognostication, and targeted treatment goals.

Reference: Gallée,J.;Cordella,C.; Fedorenko, E.; Hochberg, D.; Touroutoglou, A.; Quimby, M.; Dickerson, B.C. Breakdowns in Informativeness of Naturalistic Speech Production in Primary Progressive Aphasia. Brain Sci. 2021,11, 130.
Using smart supportive technology to explore nighttime rest in persons living with dementia
Authors: Hamza Myriam , Ault Laura , Tan Patrick , Wallace Bruce , Thomas Neil W. , Goubran Rafik , Knoefel Frank
Published: June 2023

Background

Sleep disturbances affect 60‐70% of persons living with dementia (PLWD) affecting prognosis and care burden. Sleep studies typically employ actigraphy, however, it is intrusive and lacks information on location. This study explores the use of ambient sensors, to compare nighttime rest patterns of higher and lower functioning PLWD.

Method

Study participants were recruited in a 16‐bed residential care setting for PLWD. Research ethics and consent were obtained. Pressure‐sensing bed mats, motion and door sensors were installed. The sensors were connected to a hub and the cloud.

Participants were divided into lower‐ and higher‐functioning groups based on interRAI Home Care scores.

An AI program created nightly summaries for each resident using the sensor: evening rest start / end time, number / duration of in room movements (iRM), and actual resting time (aRT) per night.

Result

The higher functioning residents (n = 7) had a mean age of 83.1 ± 11.0 years, as compared to the lower functioning group (n = 5): 85.0 ± 6.7 years. The lower functioning group had consistently higher mean interRAI scores and tended to have a greater number of medications.

Preliminary data from 407 nights suggest that the total rest time was longer for the lower functioning group (12.3+/‐0.97 hr) than the higher functioning group (11.9 +/‐ 1.24 hrs). The lower functioning group had 1.83 +/‐ 1.86 iRMs per night, with an average duration of 13.8 +/‐ 11.0 mins. The higher functioning group had 3.34 +/‐ 2.12 iRMs per night, with an average duration of 15.2 +/‐ 9.3 mins. This resulted in an aRT of 11.8 +/‐ 1.04 hrs for the lower functioning group and 11.1 +/‐ 1.25 hrs for the higher functioning group.

Conclusion

Ambient sensors were used to collect longitudinal data on nighttime activities in PLWD within a communal living setting. The findings suggest evening rest differences between higher‐ and lower‐functioning PLWD. Residents with more advanced dementia appear to be resting more, and those with less impairment seem to have more and longer rest interruptions. This technology could be used to explore the usefulness of various interventions on rest quality.
Higher proportion of visceral adipose tissue is associated with smaller regional brain volumes in older adults with type 2 diabetes: Triglycerides may be in the pathway
Authors: Boccara Ethel , Ganmore Ithamar , Ravona‐Springer Ramit , Golan Sapir , Ben‐Meir Mery , Livny Abigail , Lesman‐Segev Orit H. , Inbar Yael , Heymann Anthony , Beeri Michal Schnaider
Published: June 2023

Background

Numerous studies have identified an increased risk for Alzheimer’s dementia (AD) in Type II Diabetes (T2D). However, the T2D biological characteristics contributing to this risk are still unknown. Adiposity assessed by body mass index (BMI) is one of the main causes of T2D and has been consistently linked to higher dementia risk, faster cognitive decline, and related neural injury. However, the contribution of fat specifically cannot be derived from BMI, which encompasses different adipose tissues, bone, and muscle mass. In this study we examined whether regional abdominal adiposity contributes to AD‐related regional brain volume and mechanism underlying it, in older adults with T2D participating in the Israel Diabetes and Cognitive Decline (IDCD) study.

Method

Regional abdominal adiposity was measured so far in 60 participants, including hepatic and pancreatic adiposity and abdominal adipose tissue (AAT), composed of subcutaneous and visceral adipose tissues (SAT and VAT). Brain volumes were assessed for regions associated with cognitive decline (hippocampus, cingulate gyrus, amygdala, and ventromedial prefrontal cortex (vmPFC)). Linear regressions examined associations of regional abdominal adiposity with regional brain volumes adjusting for sociodemographics, BMI and intracranial volume. We also tested if triglycerides, the main components of fat and associated with dementia risk, mediated these associations.

Result

Greater VAT:AAT ratio was associated with smaller volumes of the vmPFC (r = ‐0.38; p = 0.026) and hippocampal (r = ‐0.44; p = 0.005) volumes but not with amygdala and cingulate gyrus volumes. The SAT:AAT ratio was associated with greater volumes of the vmPFC (r = 0.40; p = 0.026) and hippocampus (r = 0.48; p = 0.004) but not with amygdala and cingulate. No associations were found between hepatic and pancreatic adiposity with brain volumes. Higher VAT:AAT ratio was associated with higher triglyceride levels (r = 0.38; p = 0.036) which in turn were associated with lower hippocampal volume (r = ‐0.45, p = 0.05). Triglycerides partially mediated the association between VAT:AAT ratio and hippocampal volume (r = ‐0.36; p = 0.03). Triglycerides did not mediate any other associations.

Conclusion

In older adults with T2D, a higher proportion of visceral fat may have a detrimental impact on brain regions relevant to cognitive functioning. Higher proportions of subcutaneous fat may have a protective role. Triglycerides, implicated in insulin resistance and chronic systemic inflammation may mediate the VAT‐hippocampus link.
Cognitive and emotional theory of mind in dementia. Impact on real life behaviors
Authors: Zegarra‐Valdivia Jonathan Adrian , Rijpma Myrthe Gwen , Shany‐Ur Tal , Kramer Joel H. , Miller Bruce L. , Rankin Katherine P
Published: June 2023

Background

Theory of mind (ToM) is a core cognitive process that allows regular socioemotional interaction in everyday life. ToM deficits may explain some essential behavior alterations in dementia, particularly in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). This study aimed to (1) identify ToM differences across dementia syndromes and (2) determine if ToM scores predict neuropsychiatric function.

Method

We evaluated 304 participants (age 64.07±9.2) divided into six groups (healthy control, NC = 41; AD = 34; behavioral variant FTD = 96; semantic aphasia; svPPA = 38, nonfluent aphasia; nfvPPA = 47, and progressive supranuclear palsy; PSP = 48) using the UCSF Emotional and Cognitive ToM Test on the TabCAT platform and comprehensive neuropsychological and neuropsychiatric testing. Pa Patients were early in their disease (Clinical Dementia Rating: 0.80±0.53). We compared ToM between groups and used regression models controlling by age and sex to determine if ToM predicted neuropsychiatric symptoms.

Result

Cognitive ToM was impaired in AD, bvFTD, svPPA, and PSP (p<0.0001), and all groups had impaired emotional ToM (p<0.0001). Both cToM and eToM performance predicted a real‐life neuropsychiatric behavior syndrome, including anxiety, apathy, disinhibition, and aberrant motor subscales scores on the Neuropsychiatric Inventory questionnaire, even after controlling for the influence of bvFTD diagnosis.

Conclusion

Cognitive and Emotional ToM are affected early in diverse dementia syndromes, and impaired ToM test performance can predict a real‐life neuropsychiatric behavior. Assessment of ToM and other aspects of social cognition can be beneficial for the early identification of behavioral alterations in dementia cases.
Inferring genetic relatedness in a large, multisite frontotemporal dementia series: Data from the ALLFTD consortium
Authors: Ramos Eliana Marisa , Wojta Kevin , Yang Zhongan , Brushaber Danielle , Foroud Tatiana M. , Forsberg Leah K. , Heuer Hilary W. , Lago Argentina Lario , Rademakers Rosa , Coppola Giovanni , Boeve Brad F. , Rosen Howard J. , Boxer Adam L. , Geschwind Daniel H. ,   ALLFTD consortium
Published: June 2023

Background

The ARTFL‐LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) research consortium is actively enrolling participants across 23 North American centers to characterize sporadic and familial frontotemporal dementia (FTD) and prepare for disease‐modifying clinical trials. The ability to identify, otherwise unknown, relatives among these participants is critical to rigorously build family structures for downstream clinical and genetic research studies.

Methods

Genome‐wide SNP genotyping data from ALLFTD participants was used to perform lineage analyses using PLINK. Briefly, QC was performed to remove individuals with low call rate and filter autosomal SNPs for missingness, allele frequency, and deviation from Hardy‐Weinberg equilibrium, before pruning SNPs for linkage disequilibrium. Identity‐by‐descent (IBD) estimates were then calculated for determining relatedness, followed by family‐network identification and pedigree reconstruction using PRIMUS.

Results

About 46% of ALLFTD participants that were genotyped and passed QC (n = 1,453) had reported a family history, while 50% (n = 721) did not and were considered sporadic. We identified a total of 460 participants that had at least one relative who was second degree or closer (PI_HAT>0.1875) based on IBD sharing, resulting in 150 family networks. This included 9 participants who self‐identified as sporadic, demonstrating the utility of direct genetic characterization to determine familiality in FTD. Most of the predicted families were associated with disease causing variants in the 3 major FTD‐causing genes: 66 families with known C9orf72 repeat expansion carriers, 35 with MAPT (including 11 families with the variant historically known as p.P301L) and 30 with GRN pathogenic variant carriers, as well as 2 families with carriers of both a C9orf72 expansion and a GRN pathogenic variant. We also identified 5 families with carriers of pathogenic variants in other familial dementia genes (2 TARDBP, 2 VCP and 1 PSEN1), as well as 12 families with yet unknown genetic etiology.

Conclusions

This dataset sets up a crucial resource to increase statistical accuracy and power in downstream association studies using the clinical, neuropsychological, neuroimaging and biomarker data currently being generated by the ALLFTD consortium. It will also facilitate genetic studies aimed at novel gene discovery, and identification of haplotypes and genetic modifiers associated with the 3 major FTD causal genes.
The state of the art exercise recommendations for older adults with cognitive impairments: A meta‐analysis of the meta‐analysis
Authors: Heyn Patricia C , Tagawa Alex , Sood Pallavi , Ng Ted K.S. , Ries Julie , Negm Ahmed
Published: June 2023

Background

There is accumulative evidence supporting the benefits of regular physical activity in improving cognition in older adults with cognitive impairments (OAwCIs). In the past decades, multiple meta‐analyses (MA) have been published, adding to the body of literature. However, there is limited information on the overall quality and synthesized results of these studies. Thus, initiating an umbrella review, our review synthesis team appraised the evidence generated from the meta‐analysis reviews that included randomized exercise trials for OAwCIs.

Method

Upon completing the Prospero registration (ID:109720), we followed the PRISMA guidelines for reviews and performed a literature search up to January 1, 2022 to identify all published meta‐analyses which used randomized controlled trial (RCT) design. Once all potential studies were identified, three reviewers screened and reviewed studies to identify included studies, three reviewers collected and validated the data, and two reviewers assess risk of bias using the AMSTAR 2. After applying the study’s a priori inclusion and exclusion criteria, we quantitatively analyzed the effects of exercise on cognitive performance in OAwCIs.

Result

Over 2000 studies were screened for inclusion, 21 MA studies met our inclusion criteria. Based on the AMSTAR 2, three studies were high quality, nine studies were moderate quality, and nine studies were low quality. The included MA evaluated 280 RCTs, which included 22,315 participants over the age of 65 years old diagnosed with mild cognitive impairment (MCI), dementia, or Alzheimer’s disease (AD). Combined exercise training paradigms averaged 188.48±40.72 minutes per week and lasted for 18.49±4.53 weeks. Exercise training significantly improved global cognitive function, with an effect size of 0.55 (95% CI = 0.36‐0.73)

Conclusion

Sustained and prolonged exercise training (cardio endurance type) might provide an attractive and effective intervention for individuals with MCI and AD. This comprehensive umbrella review of meta‐analyses offers valuable and strong evidence‐based exercise recommendations for OAwCIs.
Gerichtete Evolution von Piperazinsäureeinbau durch eine Nichtribosomale Peptidsynthetase**
Authors: Stephan Philipp , Langley Chloe , Winkler Daniela , Basquin Jérôme , Caputi Lorenzo , O'Connor Sarah E. , Kries Hajo
Published: June 2023

Das Engineering biosynthetischer Enzyme wird zunehmend eingesetzt, um strukturelle Analoga von Antibiotika zu synthetisieren. Von besonderem Interesse sind nichtribosomale Peptidsynthetasen (NRPS), die für die Produktion wichtiger antimikrobieller Peptide verantwortlich sind. Hier beschreiben wir, wie durch gerichtete Evolution einer Adenylierungsdomäne eines Pro‐spezifischen NRPS‐Moduls dessen Substratspezifität vollständig auf die Nicht‐Standard‐Aminosäure Piperazinsäure (Piz) geändert wurde, welche eine labile N−N‐Bindung enthält. Dieser Erfolg wurde durch UPLC‐MS/MS‐basiertes Screening kleiner, rational konzipierter Mutantenbibliotheken erzielt und kann vermutlich mit einer größeren Anzahl von Substraten und NRPS‐Modulen repliziert werden. Die evolvierte NRPS ist in der Lage, ein Piz‐beinhaltendes Gramicidin S‐Analogon zu produzieren. Damit geben wir der zu früh verworfenen Idee neuen Auftrieb, dass weithin zugängliche Methoden mit niedrigem Durchsatz die Spezifität von NRPS in einer biosynthetisch nützlichen Weise verändern können.
Synergic Electron and Defect Compensation Minimizes Voltage Loss in Lead‐Free Perovskite Solar Cells
Authors: Liu Gengling , Jiang Xianyuan , Feng Wenhuai , Yang Guo , Chen Xi , Ning Zhijun , Wu Wu‐Qiang
Published: June 2023

Sn perovskite solar cells have been regarded as one of the most promising alternatives to the Pb‐based counterparts due to their low toxicity and excellent optoelectronic properties. However, the Sn perovskites are notorious to feature heavy p‐doping characteristics and possess abundant vacancy defects, which result in under‐optimized interfacial energy level alignment and severe nonradiative recombination. Here, we reported a synergic “electron and defect compensation” strategy to simultaneously modulate the electronic structures and defect profiles of Sn perovskites via incorporating a traced amount (0.1 mol %) of heterovalent metal halide salts. Consequently, the doping level of modified Sn perovskites was altered from heavy p‐type to weak p‐type (i.e. up‐shifting the Fermi level by ∼0.12 eV) that determinately reducing the barrier of interfacial charge extraction and effectively suppressing the charge recombination loss throughout the bulk perovskite film and at relevant interfaces. Pioneeringly, the resultant device modified with electron and defect compensation realized a champion efficiency of 14.02 %, which is ∼46 % higher than that of control device (9.56 %). Notably, a record‐high photovoltage of 1.013 V was attained, corresponding to the lowest voltage deficit of 0.38 eV reported to date, and narrowing the gap with Pb‐based analogues (∼0.30 V).
Phosphine‐Triggered Structural Defects in Au44 Homologues Boost Electrocatalytic CO2 Reduction
Authors: Zhuang Shengli , Chen Dong , Ng Wai‐Pan , Liu Li‐Juan , Sun Meng‐Ying , Liu Dongyi , Nawaz Tehseen , Xia Qi , Wu Xia , Huang Yong‐Liang , Lee Seungkyu , Yang Jun , Yang Jun , He Jian
Published: June 2023

The systematic induction of structural defects at the atomic level is crucial to metal nanocluster research because it endows cluster‐based catalysts with highly reactive centers and allows for a comprehensive investigation of viable reaction pathways. Herein, by substituting neutral phosphine ligands for surface anionic thiolate ligands, we establish that one or two Au3 triangular units can be successfully introduced into the double‐stranded helical kernel of Au44(TBBT)28, where TBBT=4‐tert‐butylbenzenethiolate, resulting in the formation of two atomically precise defective Au44 nanoclusters. Along with the regular face‐centered‐cubic (fcc) nanocluster, the first series of mixed‐ligand cluster homologues is identified, with a unified formula of Au44(PPh3)n(TBBT)28−2n (n=0–2). The Au44(PPh3)(TBBT)26 nanocluster having major structural defects at the bottom of the fcc lattice demonstrates superior electrocatalytic performance in the CO2 reduction to CO. Density functional theory calculations indicate that the active site near the defects significantly lowers the free energy for the *COOH formation, the rate‐determining step in the whole catalytic process.
Prevalence of gastrointestinal symptoms among autistic individuals, with and without co‐occurring intellectual disability
Authors: Holingue Calliope , Pfeiffer Danika , Ludwig Natasha N. , Reetzke Rachel , Hong Ji Su , Kalb Luther G. , Landa Rebecca
Published: June 2023

Gastrointestinal symptoms (GI) are very common among individuals on the autism spectrum. Prior research reports mixed findings regarding whether individuals with autism and co‐occurring intellectual disability (ID) have elevated risk of gastrointestinal symptoms relative to individuals with autism alone. GI symptoms can be challenging to assess in individuals with autism spectrum disorder (ASD) and/or ID given challenges with language, communication, and interoception. Prior research has tended to only include individuals with documented presence or absence of GI symptoms or conditions, that is, to exclude observations in which there is uncertainty regarding presence of GI symptoms. Therefore, none of the prior autism studies reported the association between ID and the certainty regarding presence or absence of GI symptoms. The objective of this study was to examine differences in parental certainty and odds of reporting gastrointestinal signs and symptoms among children on the autism spectrum, with and without intellectual disability. Participants were 308 children (36% ID) with a clinical diagnosis of autism spectrum disorder (6–17 years). Parents endorsed whether their child had experienced or displayed a range of signs or symptoms related to GI problems in the past 3 months. Parents of autistic children with ID were less certain about the presence of more subjective symptoms, including abdominal pain, nausea, and bloating. Conversely, certainty regarding more objective signs (e.g., constipation, diarrhea, spitting up, etc.) was not significantly different. More accurate measures for GI signs/symptoms are needed for this population.
Comparison of tyrosine kinase inhibitors in the treatment of metastatic renal cell carcinoma with rhabdoid and sarcomatoid differentiations
Authors: Wang Kun , Duan Pengqiang , Chen Xusheng , Yang Qing , Feng Guowei , Diao Lei , Zhang Zhenting , Yao Xin
Published: June 2023

Objective

To investigate the efficacy of tyrosine kinase inhibitors (TKIs) in the treatment of metastatic renal cell carcinoma (mRCC) with rhabdoid (mRCC‐R) and sarcomatoid (mRCC‐S) differentiations.

Materials and Methods

In this single‐institutional cohort study, we included patients with RCC with rhabdoid (RCC‐R) and sarcomatoid (RCC‐S) differentiation, who were treated with TKIs after metastasis at our institute from 2013 to 2021. Patient characteristics, treatments, and clinical outcomes were recorded and analyzed.

Results

We identified 111 patients with RCC‐R or RCC‐S differentiations, of which 23 patients were included in the final analysis. Of the 23 patients, 10 (43.5%) were grouped as mRCC‐R and 13 (56.5%) as mRCC‐S. At a median follow‐up of 40 months, mRCC‐R and mRCC‐S progressed in 7 of 10 and 12 of 13 patients, respectively. In addition, four and eight patients died in the mRCC‐R and mRCC‐S groups, respectively. The median progression‐free survival (PFS) of the two groups was 19 months (mRCC‐R: 95% confidence interval [CI] 4.08–33.92) and 7 months (mRCC‐S: 95% CI 2.03–11.96), while the median overall survival (OS) was 32 months and 21 months, respectively. mRCC‐S had a worse prognosis than mRCC‐R. Based on the univariate Cox regression model, single metastasis or multiple metastasis of tumor, rhabdoid differentiation, and sarcomatoid differentiation were predictors of PFS but not OS.

Conclusion

The efficacy of TKIs in the treatment of mRCC‐R and mRCC‐S may be different.
Radiological‐histopathological discordance in patients transplanted for HCC and its impact on post‐transplant outcomes
Authors: Mohamed Islam B. , Ismail Mohamed Saleh , El Sabagh Ahmed , Afifi Abdelwahab Ahmed M. , Polychronopoulou Efstathia , Kuo Yong‐Fang , Hassan Manal , Goss John A. , Kanwal Fasiha , Jalal Prasun K.
Published: June 2023

Background and Aims

Contrast‐enhanced cross‐sectional imaging is the cornerstone in the diagnosis, staging, and management of HCC, including eligibility for liver transplantation (LT). Radiological‐histopathological discordance may lead to improper staging and may impact patient outcomes. We aimed to assess the radiological‐histopathological discordance at the time of LT in HCC patients and its impact on the post‐LT outcomes.

Methods

We analyzed further the effect of 6‐month waiting policy on the discordance. Using United Network for Organ Sharing—Organ Procurement and Transplantation Network (UNOS‐OPTN) database, we examined the discordance between pre‐LT imaging and explant histopathology for all adult HCC patients who received liver transplants from deceased donors between April 2012 and December 2017. Kaplan–Meier methods and Cox regression analyses were used to evaluate the impact of discordance on 3‐year HCC recurrence and mortality.

Results

Of 6842 patients included in the study, 66.7% were within Milan criteria on both imaging and explant histopathology, and 33.3% were within the Milan based on imaging but extended beyond Milan on explant histopathology. Male gender, increasing numbers of tumors, bilobar distribution, larger tumor size, and increasing AFP are associated with increased discordance. Post‐LT HCC recurrence and death were significantly higher in patients who were discordant, with histopathology beyond Milan (adj HR 1.86, 95% CI 1.32–2.63 for mortality and 1.32, 95% CI 1.03–1.70 for recurrence). Graft allocation policy with 6‐month waiting time led to increased discordance (OR 1.19, CI 1.01–1.41), although it did not impact post‐LT outcome.

Conclusion

Current practice for staging of HCC based on radiological imaging features alone results in underestimation of HCC burden in one out of three patients with HCC. This discordance is associated with a higher risk of post‐LT HCC recurrence and mortality. These patients will need enhanced surveillance to optimize patient selection and aggressive LRT to reduce post‐LT recurrence and increase survival.
Mental health care utilization among men with castration‐resistant prostate cancer receiving abiraterone or enzalutamide
Authors: Tsao Phoebe A. , Burns Jennifer , Kumbier Kyle , Sparks Jordan B. , Entenman Shami , Bloor Lindsey E. , Bohnert Amy S. B. , Skolarus Ted A. , Caram Megan E. V.
Published: June 2023

Background

Abiraterone and enzalutamide are castration‐resistant prostate cancer (CRPC) therapies with potentially distinct associations with mental health symptoms given their differing antiandrogen targets.

Methods

We used national Veterans Health Administration data to identify patients with CRPC who received first‐line abiraterone or enzalutamide from 2010 to 2017. Using Poisson regression, we compared outpatient mental health encounters per 100 patient‐months on drug between the abiraterone and enzalutamide cohorts adjusting for patient factors (e.g., age). We compared mental health encounters in the year before versus after starting therapy using the McNemar test.

Results

We identified 2902 CRPC patients who received abiraterone (n = 1992) or enzalutamide (n = 910). We found no difference in outpatient mental health encounters between the two groups (adjusted incident rate ratio [aIRR] 1.04, 95% confidence interval [CI] 0.95–1.15). However, men with preexisting mental health diagnoses received 81.3% of the outpatient mental health encounters and had higher rates of these encounters with enzalutamide (aIRR 1.21, 95% CI 1.09–1.34). Among patients with ≥1 year of enrollment before and after starting abiraterone (n = 1139) or enzalutamide (n = 446), there was no difference in mental health care utilization before versus after starting treatment (17.0% of patients vs. 17.6%, p = 0.60, abiraterone; 16.4% vs. 18.4%, p = 0.26, enzalutamide).

Conclusion

We found no overall differences in mental health care utilization between CRPC patients who received first‐line abiraterone versus enzalutamide. However, men with preexisting mental health diagnoses received the majority of mental health care and had more mental health visits with enzalutamide.
Efficacy and safety of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of esophageal squamous cell cancer: A prospective, open label, randomized phase II study
Authors: Dai Xichao , Tao Leilei , Wang Jinqiu , Wu Wenjuan , Bian Weigang , Dai Xichun , Chen Surong
Published: June 2023

Background: Esophageal squamous cell cancer (ESCC) accounts for approximately 90% of esophageal cancer cases in China. There are no standard regimens for second or third–line chemotherapy of metastatic squamous esophageal cancer. The objective of this study was to investigate the security and effectiveness of irinotecan combined with raltitrexed or irinotecan monotherapy for salvage chemotherapy of ESCC.

Methods: One hundred and twenty–eight patients with metastatic ESCC confirmed by histopathology were enrolled into this study. These patients had failure of the first–line chemotherapy combination of fluorouracil or platinum or paclitaxel and had not undergone chemotherapy with irinotecan or raltitrexed previously. Patients were randomly divided into irinotecan combined with raltitrexed group (experiment group) and irinotecan monotherapy group (control group). Overall survival (OS) and progression–free survival (PFS) were the primary endpoint.

Results: In the control group, the median PFS (mPFS) and median OS (mOS) of patients were 3.37 and 5.3 months. In the experiment group, mPFS and mOS were 3.91 and 7.0 months. There was statistical significance of PFS and OS between two groups (PFS P = 0.002, OS P = 0.01). In subgroup analysis, in the second–line treatment, the mPFS of control and experiment group, was 3.90 and 4.60 months, mOS was 6.95 and 8.5 months, which was statistically significant differences between the two groups. (PFS P = 0.001, OS P = 0.005), In the third–line and beyond treatment, mPFS of control and experiment group was 2.80 and 3.19 months, mOS were 4.5 and 4.8 months. But there was no significant difference of PFS or OS between the two groups (PFS P = 0.19, OS P = 0.31). There was no statistical significance of toxicity side effects between two groups.

Conclusions: The PFS and OS of irinotecan plus raltitrexed may be better than that of irinotecan monotherapy, especially in second line treatment, which should be confirmed with a phase III study including much more patients.
Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid‐derived suppressor cells in hepatocellular carcinoma
Authors: Liu Yun , Chen Xi , Luo Wenwu , Zhao Yufei , Nashan Björn , Huang Lei , Yuan Xiaodong
Published: June 2023

Background

Preclinical studies and clinical trials have demonstrated that tumor‐intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle‐related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC).

Method and Results

Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non‐negative matrix factorization algorithm. Multivariable‐adjusted Cox regression analysis indicated that the cell cycle gene‐based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression‐free interval time was associated with activated cell cycle program, higher infiltration of myeloid‐derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three‐gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle‐based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+CD33+HLA‐DR−MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte‐mediated immunity, natural killer cell‐mediated immunity, interferon‐gamma production, T‐cell activation, and T‐cell‐mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC.

Conclusion

Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.