bluuebunny/crossref_metadata_2025 huggingface dataset:
TDP‐43 promotes pathological tau phosphorylation and selective neurotoxicity in C. elegans
Authors: Latimer Caitlin S. , Keene C. Dirk , Kraemer Brian C , Liachko Nicole F
Published: December 2021

Background

TDP‐43‐positive inclusions are present in disease‐affected neurons in over half of patients with Alzheimer’s disease (AD). AD patients with TDP‐43 pathology have worsened clinical outcomes and increased neurodegeneration, but the molecular mechanisms underlying this are unknown.

Methods

We have developed new models of multi‐pathology AD by combining tau and TDP‐43 or tau and Aβ in C. elegans neurons. To characterize these transgenic animals, we measured changes in behavioral outcomes, pathological protein accumulation, and neuron loss. We further tested whether the potent tau modifier sut‐2 influences synergistic neurotoxicity exhibited by tau and TDP‐43 co‐expression.

Results

TDP‐43 promotes tau but not Aβ neurotoxicity, resulting in enhanced uncoordinated locomotion, neuronal dysfunction, pathological protein accumulation, and selective neurodegeneration through aging. Synergism between tau and TDP‐43 is rescued by sut‐2 loss‐of‐function.

Conclusions

Characterizing the relationship between TDP‐43 and tau in vivo is critical to understand and ultimately treat mixed pathology AD. Studies of this novel model of tau and TDP‐43 combined proteotoxicity provide insights into mechanisms underlying tau and TDP‐43 synergistic neurotoxicity. The identification of sut‐2 as a robust modifier of co‐expressed tau and TDP‐43 implicates TDP‐43 as an enhancer of tau toxicity.
Assessing therapeutic potential of PLD1 inhibition in dementia: Systematic assessment of behavior, electrophysiology & mechanisms of synaptic dysfunction using different parameters including sex‐specific differences
Authors: Natarajan Chandramouli , Bourne Krystyn Z , Ramaswamy Karthik , Cook Charles M , Krishnan Balaji
Published: December 2021

Background

Phosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.

Methods

We used different transgenic rodent models of AD‐like pathology and did a corroborative assessment of behavior, electrophysiology and biochemistry including western blots analysis, Golgi studies and immunofluorescence to assess the efficacy of treatment of the aberrantly elevated PLD1 levels using chronic regimen of a specific small molecule inhibitor.

Result

Chronic PLD1 inhibition is effective in ameliorating the synaptic dysfunction and associated memory deficits in the treated cohort compared to the age‐matched cohort. We also assessed and report sex‐specific changes in these responses that strengthen our understanding of the underlying mechanisms and brain regions that are targeted by the therapeutic approaches.

Conclusion

Using chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory with an emphasis on the sex‐specific effects.
Autophagy and lysosomal defects in cells expressing disease‐associated tau
Authors: Pollack Saskia J , Dakkak Dina , Guo Tong , Gómez‐Suaga Patricia , Noble Wendy , Hanger Diane P
Published: December 2021

Background

Intracellular accumulation of insoluble tau is an important hallmark of Alzheimer’s disease (AD) and related tauopathies. We have previously identified in human tauopathy brain a truncated tau species (Tau35), comprising the C‐terminal half with four microtubule‐binding repeats. Minimal Tau35 expression in transgenic mice results in a progressive tauopathy phenotype including tau phosphorylation and aggregation, cognitive and behavioural abnormalities and impaired protein clearance. The autophagy‐lysosomal pathway (ALP) plays a crucial role in the clearance of protein aggregates and defects in ALP are associated with the pathogenesis of AD. We sought to explore the effect of Tau35 expression on the ALP and whether autophagy is disrupted due to lysosomal dysfunction.

Method

Chinese hamster ovary (CHO) cells stably expressing Tau35 (CHO‐Tau35) or full‐length human 2N4R tau (CHO‐FL) were generated. Primary cortical neurons from Tau35 transgenic and wild‐type mice were cultured for 14 days in vitro(DIV) and brain homogenates were prepared from mice aged 4 and 12 months. The effect of Tau35 on the ALP was examined using immunofluorescence and western blots.

Result

Nuclear translocation of transcription factor EB (TFEB), a key mediator of lysosomal biogenesis, was significantly reduced in both CHO‐FL and CHO‐Tau35 cells. However, only CHO‐Tau35 cells exhibited disrupted mammalian target of rapamycin complex 1 (mTORC1) activity and autophagic flux. Expression of ALP markers, including LC3‐I/II, LAMP1, LAMP2 and cathepsin D, were also reduced in CHO‐Tau35 cells.

Conclusion

Our findings suggest that N‐terminally cleaved tau damages both lysosomal clearance of cellular proteins and lysosomal biogenesis. The Tau35‐expressing cultured neurons will provide a useful tool to explore molecular mechanisms underlying tau‐induced lysosomal dysfunction, which may lead to the identification of novel therapeutic targets for dementia.
Therapeutic investigation of alpha napthoflavone in the intracerebroventricular injection of L‐cysteine induced vascular dementia in rats
Authors: Rishitha Narahari , Muthuraman Arunachalam
Published: December 2021

Background

Alpha napthoflavone (ANF) is a flavonoid compound it is also know as Alpha‐ 7,8‐benzoflavone, it is a natural flavone available in Russian knapweed in larger quantity. Pharmacologically, it is also reported to produce the cardioprotection, neuroprotection including anti‐Alzheimer actions. It possesses multiple cellular actions like anti‐oxidant, anti‐inflammatory, and anti‐apoptotic actions. However, the role of ANF in vascular dementia (VaD) not explored yet.

Method

VaD was induced by i.c.v. injection of L‐Cys in rats. The test compounds i.e., ANF (40 and 80 mg/kg; p.o.) and reference drug i.e., donepezil (10 mg/kg; p.o.) were administered for 5 consecutive days. The behavioral assessment i.e., learning and memory functions were evaluated by Morris water maze (MWM) test. In addition, the biochemical markers i.e., acetylcholinesterase (AChE) activity; lipid peroxidation (LPO) and homocysteine (HCy) levels were estimated in hippocampal tissue samples

Result

ANF shown ameliorative effect against i.c.v. injection of L‐Cys induced VaD in rats via reduction of AChE activity, LPO and HCy levels

Conclusion

ANF may be a newer candidate from herbal origin for the management of cerebrovascular disorders like stroke and vascular dementia.
Regional abdominal adiposity and related factors are associated with brain volumes and cognitive functioning in middle‐aged adults at high AD‐risk
Authors: Golan Sapir , Boccara Ethel , Ravona‐Springer Ramit , Inbar Yael , Livny Abigail , Yore Iscka , Heymann Anthony , Beeri Michal Schnaider
Published: December 2021

Background

Alzheimer’s dementia (AD) is one of the most challenging diseases, affecting individuals, their families, and society. There is evidence for the involvement of midlife obesity (measured by BMI) in mild cognitive impairment (MCI), dementia, and AD risk in late life. Regional abdominal adiposity has been related to metabolic syndrome and inflammation, both consistently linked to cognitive impairment and neuropathology of AD. The accelerating prevalence of obesity and dementia in our aging population further amplifies the potential public health impact of the proposed investigation.

Method

The Israel Registry for Alzheimer’s Prevention (IRAP) (N=500), which aims to examine the connection between longevity and dementia, was capitalized. Newly collected data ‐ regional abdominal adiposity (abdominal (AAT) visceral (VAT), subcutaneous (SAT), pancreatic, and hepatic adipose tissue) by MRI (N=92), and adiposity‐related factors of visceral fat (TNF‐α, Leptin), pancreases (PP, PYY), and liver (PAI‐1, Fetuin) via serum (N=26).

Result

High pancreatic fat percentage was associated with lower hippocampal and IFG volumes, and lower executive memory function. High hepatic fat percentage was associated with lower hippocampal volume and lower executive memory function. High VAT percentage was associated with lower amygdalar and hippocampal volumes, while high VAT volume was associated with lower cognitive functioning (executive and working memory, language, and global cognition). Serum levels of PP, PAI‐1, and Fetuin were negatively associated with para‐hippocampal and IFG volumes. Serum levels of Leptin were associated with amygdala and hippocampal volumes. High levels of PYY, PAI‐1, and TNF‐α were associated with lower executive memory function.

Conclusion

Greater regional abdominal adiposity and related secreted factors are associated with poorer cognitive functions and lower volumes of cognition and BMI‐related brain regions, already in midlife in asymptomatic individuals enriched for AD risk, regardless of global body adiposity measured by BMI. These results strongly support our overall hypothesis that specific fat deposits in specific tissues and organs are differentially associated with cerebrovascular and AD‐related neuropathology and cognition, advancing the field to new potential mechanistic pathways underlying the adipose tissue‐brain link.
Learning deficits occurs prior to memory retrieval impairment in female Senescence Accelerated Mouse (SAMP8)
Authors: Sun Jiaqi , Mamo John CL , Takechi Ryu , Owada Yuji , Nicolazzo Joseph , Pan Yijun
Published: December 2021

Background

The most regularly used mouse models of Alzheimer's disease in drug development include APP/PS1, 3xTg, and 5xFAD mice. This is a limitation as all these mice represent familial AD. Given sporadic AD accounts for the majority of the AD cases in human, there is an unmet need to validate potential rodent models to better represent sporadic AD. SAMP8 is a naturally‐occurring mouse line that displays many characteristics identified in Alzheimer’s disease (AD) patients, such as learning and memory deficits, and accumulation of beta‐amyloid. In people with preclinical AD, deficits in learning manifest faster than decline in memory retrieval. It is unclear if SAMP8 mice also exhibit this feature, and therefore the current study aims to determine if this feature can be observed in SAMP8, to support the use of SAMP8 as a mouse model of sporadic AD for drug development.

Method

The cognitive function of SAMP8 mice and their age‐matched non‐AD control SAMR1 mice (at various ages) were assessed using Y maze spatial memory test, with 3‐10 min training duration and 1.5‐3 h interval between training and testing session.

Result

At 3‐4 months old, SAMP8 but not SAMR1 failed to differentiate the novel arm from familiar arm in a standard Y maze test (3 min training, 3 h interval). When training time was increased to 10 min, SAMP8 passed the test, while increased training time did not affect the performance of SAMR1 mice. These data indicated that longer training time is required by SAMP8 than SAMR1 to achieve the expected performance, suggesting the presence of learning deficits in SAMP8. Interestingly, at 6‐7 months old, though both SAMP8 and SAMR1 received 10‐min training, only SAMR1 passed the test. The performance of SAMP8 mice was successfully improved by shortening the interval between training and testing (from 3 h to 1.5 hr). These data indicate a deteriorated memory retention capability and a possible impairment in memory retrieval in SAMP8.

Conclusion

Overall, this study has provided supportive evidence that learning deficits occurs prior to memory retrieval impairment in SAMP8, and the use of SAMP8 as mouse model for AD.
In silico screening of existing FDA approved drugs for spermine synthase inhibition as a therapeutic approach in Alzheimer’s disease
Authors: Wilson Joel , Nampoothiri Madhavan , Satarker Sairaj
Published: December 2021

Background

Autophagy dysfunction may lead to amyloid‐β (Aβ) secretion and directly influence the accumulation of intracellular Aβ and generation of extracellular Aβ plaque. Natural polyamine, spermidine present in all living organisms, is critically involved in cellular homeostasis maintenance and influences many biological processes, namely cell growth and proliferation, DNA and RNA stabilization, tissue regeneration, regulation of translation, and enzymatic modulation. Brain spermidine/polyamine levels decrease during aging and various neurodegenerative disorders leading to impairment in autophagy. Spermine synthase is an enzyme involved in biosynthesis of polyamines. It catalyzes the formation of spermine from spermidine. Thus, we focused to repurpose USFDA approved drugs to inhibit spermine synthase which may increase the spermidine levels in the brain.

Method

Schrodinger Suite's Maestro graphical user interface was used to carry out computational simulation experiments. Spermidine structure and US‐FDA licensed molecules compounds were downloaded. The molecules were configured using LigPrep tool in maestro software of Schrodinger. Spermine synthase structure (3C6K) bound to 5‐methylthioadenosine (MTA) was downloaded from Protein Data Bank (PDB). After the protein was minimized, the 2D interaction of the ligand‐protein interaction was conducted to observe the amino acid interactions. Spermidine and USFDA licensed molecules were docked using the Schrodinger Glide module. In the present study, the MMGBSA tool is utilized to calculate the prediction of the top compounds. The MD simulation was performed on Schrodinger's Desmond module.

Result

For increasing spermidine pool in the brain by inhibiting spermine synthase, Ribavirin, Sapropterin and Theobromine were found to cross the BBB and have good inhibitory interactions with the enzyme in an in‐silico system. RMSD values for all these three drugs were not satisfactory, but other parameters like protein‐ligand contact‐interaction fraction, 2D interaction diagram and protein‐Ligand contacts through different amino acids present in 3C6K showed satisfactory results.

Conclusion

Our study showed that ribavirin, sapropterin and theobromine were able to show inhibitory interactions with the spermine synthase. Further, in vitro and in vivo studies may be done to search for the ability of these molecules in the treatment of cognitive dysfunction.
Functional study in the young rTg4510 mouse model of tauopathy
Authors: Mondragón‐Rodríguez Siddhartha , Cueva‐Xolalpa Lorena , García‐Carlos Carlos , Villaseñor‐Zepeda Rocío , Orta‐Salazar Erika , Díaz‐Cintra Sofia , Peña‐Ortega Fernando , Perry George
Published: December 2021

Background

Tau hyperphosphorylation (pTau) is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, pTau promotes neuroprotection by preventing seizure‐like activity.

Method

To further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (p30‐35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function.

Result

Our results showed that the very young rTg4510 model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from p30‐35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found an increased number of dendrites per cell in granule neurons.

Conclusion

Altogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.
Role of endothelial TRPA1 expression in blood‐brain barrier dysfunction
Authors: Yang Euitaek , Kaddoumi Amal
Published: December 2021

Background

Transient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel receptor that regulate calcium homeostasis among other cations. Calcium dyshomeostasis known to disrupt the blood‐brain barrier (BBB). In the brains of Alzheimer's disease (AD) transgenic mice, increased levels of TRPA1 was associated with increased levels of amyloid‐β (Aβ) and neuroinflammation. TRPA1 expressed in the endothelial cells of the BBB. The objective of this work is to investigate the effect of BBB‐endothelium TRPA1 activation on the BBB tightness and function.

Method

We performed in vitro and in vivo studies, Western blot, calcium assay, immunostaining.

Result

We performed in vitro studies using the mouse brain endothelial cell line bEnd3. First, we determined the expression of TRPA1 in bEnd3 by western blot and immunocytochemistry. Results confirmed TRPA1 expression in bEnd3. In addition, TRPA1 function was evaluated by monitoring calcium influx; the addition of the TRPA1 antagonist A‐967079 significantly reduced calcium influx in bEnd3, while the addition of Aβ42 oligomers to the cells increased intracellular calcium levels, which was blocked by the co‐addition of the TRPA1 antagonist suggesting that Aβ induces calcium influx via TRPA1. When tested in vivo in 5XFAD mouse model for AD by western blot, we found that TRPA1 levels were significantly higher in brain homogenates when compared to wild‐type (WT) mouse brains. Furthermore, the cerebrovascular levels of TRPA1 were significantly higher in 5XFAD compared to WT, which were also associated with BBB disruption as determined by increased IgG extravasation.

Conclusion

Our data suggests that endothelium‐TRPA1 could contribute to BBB disruption by increasing calcium influx.
Dynamics between Neuropsychiatric Symptoms and Biomarkers: A Pilot Study
Authors: Chiu Wei‐Hsuan , Goh Anita M Y , Velakoulis Dennis , Loi Samantha M
Published: December 2021

Background

The aetiology of neuropsychiatric symptoms (NPS) in dementia remains unclear, and currently, it is challenging to distinguish neuropsychiatric manifestations related to younger‐onset neurodegenerative diseases from those of primary psychiatric disorders. Neurofilament light chain (NfL) is a promising biomarker for axonal injury and has been found to differentiate between neurodegenerative diseases and primary psychiatric disorders. The aim was to investigate cerebrospinal fluid (CSF) NfL and its relationship with NPS and compare it with traditional biomarkers, namely Aβ and tau.

Methods

Retrospective data for 54 patients with younger‐onset dementia was collated (mean age ± SD, 57.9 ± 7.1, females n = 15 [28%], co‐morbid psychiatric diagnoses n = 17 [31%]). Of these, 23 had Alzheimer’s disease (AD), 14 had frontotemporal dementia (FTD), 9 had mild cognitive impairment (MCI), and 8 were diagnosed with other types of dementia. Neuropsychiatric measures were extracted from the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), the Depression Anxiety and Stress Scale 21 (DASS‐21), and the revised Cambridge Behavioural Inventory (CBI‐R). CSF biomarkers included NfL, Ab‐42, p‐tau and t‐tau.

Results

No significant associations between NPS and NfL was seen in patients with AD, FTD, MCI or other diagnoses. In the combined cohort, a positive correlation was found between the overall cognitive functioning and Ab‐42 levels (r = 0.47, p = 0.01), and visuoconstruction, a specific domain of cognitive functioning, was found to be positively correlated with Ab‐42 levels (r = 0.44, p = 0.03) and negatively correlated with t‐tau levels (r = ‐0.43, p = 0.03). In FTD, a positive correlation was found between stress and p‐tau levels (n = 8, r = 0.89, p = 0.04), and this correlation was stronger in patients without co‐morbid psychiatric diagnoses (n = 7, r = 0.93, p = 0.03).

Conclusion

The results suggest that levels of CSF biomarkers, especially Ab‐42, are linked to deficits in cognitive functioning in patients with younger‐onset dementia, and levels of p‐tau are strongly related to stress particularly in the absence of co‐morbid psychiatric diagnoses. Therefore, these biomarkers may assist in the identification of patients who are at an increased risk of developing cognitive impairment and stress.
The impact of presentation modality on cognitive test performance for adults with hearing loss
Authors: Goodwin Maria V , Hogervorst Eef , Maidment David W
Published: December 2021

Background

There is a growing body of evidence demonstrating hearing loss in middle‐aged and older adults is independently associated with an increased risk of developing cognitive‐decline and dementia. Verbal memory is one of the most common functions to decline early in Alzheimer’s disease, the most common form of dementia Whilst the exact mechanisms underlying this association remain unclear, poorer test performance may reflect an overarching sensory deficit, as, for instance, most verbal memory tests are predominantly delivered auditorily. Therefore, this study aimed to investigate whether different modes of presentation (i.e., visual, or auditory) influence verbal memory screening test performance in those who failed a hearing screener.

Method

The study was conducted via online video‐conferencing due to the COVID‐19 pandemic. Participants (N= 63) completed a validated hearing screener, which was a digit‐in‐noise test delivered via the hearWHO smartphone application. Three cognitive tests were also administered: (1) the Modified Telephone Interview for Cognitive Status (TICS‐M), presented auditorily; (2) the Hopkins Verbal Learning Test (HVLT), presented visually; and (3) a verbal fluency task as a control. All tests have been used as dementia screening tests.

Result

Separate ANCOVAs revealed that, when controlling for age, gender, and education level, adults who failed the hearing screener performed more poorly on the TICS‐M compared to individuals who passed (p<.001). No differences between hearing groups were found for the other cognitive tests administered (p≥ .132).

Conclusion

This study provides support for the notion that the presentation mode of cognitive tests may account for some of the deficits observed in older adults with hearing loss. As such, researchers and clinicians should be mindful of the sensory deficits experienced by individuals when interpreting cognitive test performance, to avoid the overestimation of cognitive deficits and dementia in adults with hearing loss.
Modeling AD‐related metabolic impairments in the TgF344‐AD rat model
Authors: Hernandez Abbi Lynn (R) , Ding Sarah L , Simley Alexis L , McMahon Lori L , Carter Christy S
Published: December 2021

Background

Alzheimer’s disease (AD) not only affects cognition and neuropathology, but has several other facets capable of negatively impacting quality of life, including impaired metabolic function, which is present in ∼80% of cases. However, the influence of metabolism is seldom considered when utilizing rodent models of AD, particularly in conjunction with cognitive impairment and neuropathology. Therefore, we characterized metabolic and cognitive status of the TgF344‐AD rat model first presented in Cohen et al. in 2013.

Method

Aged (20‐26 mo) female rats were utilized. Metabolic health was characterized through body composition analysis, food consumption quantification, insulin and glucose tolerance tests and hypothalamic p‐AKT/AKT response to insulin. Cognition was assessed through object discrimination tasks, including novel object discrimination, working memory/object discrimination and working memory/biconditional association tasks. This series of increasingly complex behavioral tasks requires proper function of individual brain regions, as well as integration of information across these regions, in which AD‐related pathology is commonly observed.

Result

AD rats required significantly more trials before reaching criterion performance across several tasks, including a working memory/object recognition task and a working memory/biconditional association task. However, there were no group differences in ability to perform a simple object discrimination, demonstrating all rats were able to participate procedurally, therefore differences in performance can be attributed to cognitive impairment. AD rats had significantly more body fat than WT, and lost significantly less weight than their wild type (WT) counterparts while relocating to our colony, despite consistent food consumption across groups. Moreover, glucose appears to be rapidly degraded in AD rats relative to WT controls, indicating significant differences in metabolic function across genotypes.

Conclusion

Together, these data indicate that not only do we observe genotype‐specific deficits in cognitive function, but also that the transgenic rats metabolize their energy sources in different ways than WT littermates. The long range projection neurons required to support task acquisition are more metabolically costly than locally projecting neurons, and thus most likely affected by the impaired metabolic function in this rats. Therefore, treatments targeting these metabolic deficits may help prevent or ameliorate AD‐related cognitive decline.
The association between proactive semantic interference and blood sugar levels
Authors: Sosa Jaylene , Amaya Alexandra C , Gonzalez‐Jimenez Christian J , Gorman Katherine , Leal Eduardo , Kitaigorodsky Marcela , Curiel Rosie E , Loewenstein David
Published: December 2021

Background

Glucose levels, together with hemoglobin A1c (HA1c), have been associated with reduced cognitive performance, particularly on executive functioning and memory measures. Numerous studies using the Loewenstein‐Acevedo Scales for Semantic Interference and Learning (LASSI‐L) have demonstrated that proactive semantic interference (PSI) and failure to recover from PSI (frPSI) are sensitive to early cognitive changes present in the preclinical stages of Alzheimer's disease (AD).

Method

The aim of the present study was to examine the association between PSI, frPSI, blood glucose levels, and hemoglobin A1c (HA1c) among cognitively normal middle‐aged adults. Seventy‐five adults (Age: 50.8 ± 6.67; Education: 16.23 ± 2.93; Sex: 68% female) without psychological disorders, substance use disorders, or previous cognitive diagnoses were recruited as part of a memory and aging study. Sixty‐seven participants identified as White (89%) and eight as African American (11%). They were fluent in English and/or Spanish and were tested in their dominant and preferred language (65% English, 35% Spanish), as assessed by the Language Experience and Proficiency Questionnaire. All participants underwent a neuropsychological evaluation and administration of the Clinical Dementia Rating Scale (CDR); all were diagnosed as cognitively normal by trained neuropsychologists. Participants fasted six to eight hours prior to providing a blood sample. Comparisons were made between participants using t‐tests and Chi‐square tests. An additional Spearman correlation was used to determine the relationship between the variables. Blood glucose and HA1c levels were compared to LASSI‐L scores, including the number of words correctly recalled and the number of intrusion errors (IE) on the PSI (List B Cued Recall 1) and frPSI (List B Cued Recall 2) trials.

Result

There was no significant association between glucose and the LASSI‐L Scales. However, higher HA1c levels were correlated with lower intrusion errors sensitive to proactive semantic interference.

Conclusion

Our findings are inconsistent with previous research, as an increase of blood glucose and HA1c levels have been formerly found to lead to reduced cognitive performance. Based on these findings, further investigations are warranted to better understand the associations between HA1C levels, proactive semantic interference, and varying cognitive domains.
Accelerated epigenetic aging in adults with Down Syndrome in the Argentine population
Authors: Clas Giulia Solange , Fernández Elmer A. , Vázquez Juan Carlos Guillermo , Pertierra Lucia , Guimet Nahuel Magrath , Tapajoz Fernanda , Helou Belén , Itzcovich Tatiana , Kennedy Micaela Barbieri , Martinetto Horacio , Sevlever Gustavo , Allegri Ricardo Francisco , Surace Ezequiel
Published: December 2021

Background

Life expectancy of individuals with Down Syndrome (DS) is currently 60 years. From age 40 they have an increased risk of dementia and almost all of them have histopathological features of Alzheimer's disease (AD) in their brains. Also, it is known that the ε4 allele of the APOE gene and the R47H variant of TREM2 increase the risk of AD. DS is also associated with a group of clinical manifestations of accelerated aging. DNA methylation‐based biomarkers of ageing (epigenetic clocks) can be assessed by different models. It is known that DNA methylation age (DNAm) has a positive correlation with chronological age in disomic individuals while DS subjects exhibit an age acceleration effect in blood and brain.

Method

We determined the DNAm age of a cohort of seven participants with chromosome 21 trisomy (confirmed by G‐banding karyotyping). Median age was 49 years. Their cognitive status was assessed by clinical and neuropsychological evaluations. AD risk variants in APOE and TREM2 were analyzed by RFLP‐PCR. DNAm age was assessed in peripheral blood leukocytes, using the Illumina 850K platform. We used the Horvath’s epigenetic clock, based on the DNAm levels of 353 specific CpG sites.

Result

Five participants exhibited the ε3/ε3 genotype in APOE and two of them the ε3/ε4 genotype. We did not observe the R47H risk variant in TREM2 in this group. Five participants showed a significant biological age acceleration and one participant’s DNAm age was similar to his chronological age. Of note, one participant showed a deceleration in the DNAm age. This participant also had multiple myeloma. It is known that the DNA methylation profile of multiple myeloma cells differs from normal plasma cells. On the other hand, we did not find a trend towards a greater presence of the risk allele ε4 or cognitive impairment in participants with a significant DNAm age acceleration.

Conclusion

The majority participants presented an acceleration in their biological age, but this fact was not correlated with a greater presence of the risk allele ε4 or cognitive impairment. This is the first dataset of DNA methylation ages of a cohort of people with Down Syndrome in Latin America.
Comparison of latent cognitive reserve markers and a latent marker score in Alzheimer’s disease
Authors: Ersoezlue Ersin , Rauchmann Boris‐Stephan , Perneczky Robert ,   Alzheimer’s Disease Neuroimaging Initiative
Published: December 2021

Background

The cognitive reserve (CR) hypothesis explains inter‐individual differences in the association between observed cognitive function and estimated neurodegenerative burden. Latent CR marker approach were suggested as a promising method to estimate cognitive reserve. We aimed to compare different CR marker approaches and test a clinical latent CR marker score.

Method

Amyloid‐β (Aβ)‐negative and cognitively normal participants were included as healthy controls (HC) and Aβ‐positive and clinically impaired participants were included as AD spectrum (ADS) from the AD Neuroimaging Initiative (ADNI) study as two separate CSF data‐only discovery and a PET data‐only replication cohorts. A latent CR marker factor (CRM‐Factor) was obtained as the latent global cognitive domain score (gCDS) through a principal component analysis remaining after accounting for neuropathological burden and demographic variables. A residual CR marker (CRM‐Residual) was calculated as residualized gCDS in a multilinear regression analysis. We then estimated a CR marker score (CRM‐Score) as predictions from a multiple regression model with CRM‐Factor as dependent variable and demographics, total Mini‐Mental State Examination score and binarized biomarker status as predictors. Markers have been derived at baseline. We tested the moderation of each CR marker on the individual trajectories of memory decline in separate linear mixed models.

Result

Higher years of education were predicted by the CR markers when tested separately. CRM‐Residual levels were strongly associated with CRM‐Factor, while CRM‐Residual was moderately associated with CRM‐Factor and CRM‐Score. In linear mixed models, patients in ADS with higher CR revealed a slower memory decline, mainly in preclinical AD.

Conclusion

Our results support the operational value and effectivity of the latent CR marker approach. We defined a novel latent CR Marker Score that may be operationalized in independent cohorts without conducting a data‐driven analysis. In line with previous studies, latent CR markers estimated differences in cognitive trajectories predominantly in the MCI stage. Our marker score approach can offer a standardized clinical scoring for simple, cohort‐independent and effective estimation the individual CR in clinical and epidemiological studies, making a better individual risk assessment and estimating therapeutic effects to strengthen the CR.
Whole Exome Sequence Study of Mild Cognitive Impairment in African and European Americans; the Atherosclerosis Risk in Communities‐Neurocognitive Study
Authors: Mahmud Shamsed , Mei Hao , Tin Adrienne , Bressler Jan , Pruett William A , Fornage Myriam , Huang Juebin , Boerwinkle Eric , Mosley Thomas H , Simino Jeannette
Published: December 2021

Background

Mild cognitive impairment (MCI) encompasses cognitive deficits beyond normal aging that minimally impact daily functioning. Uncovering the genetic architecture of MCI, which can progress to Alzheimer’s disease in some individuals, may facilitate the development of lifestyle and pharmacologic interventions to minimize cognitive impairment or prevent dementia. We conducted a whole exome sequence study of MCI in 1,144 African American (AA) and 3,358 European American (EA) participants aged 67‐90 years from the Atherosclerosis Risk in Communities‐Neurocognitive Study.

Methods

For both single‐variant and gene‐based tests, we employed seqMeta to perform race‐stratified analyses of functional (nonsynonymous, splicing, stopgain, stoploss, or frameshift) variants in each sex alone and both sexes combined. Models were adjusted for age, sex (except sex‐stratified models), field center, and population substructure (the first ten principal components). Logistic regression models were fit on autosomal single‐variants with minor allele frequency (MAF) ≥0.01 while SKAT‐O, T1 burden, and SKAT (beta weights and MAF ≤ 0.05) gene‐based tests were conducted. The significance and suggestive p‐value thresholds were 1.13E‐06 and 2.27E‐05 for single‐variant tests and 2.81E‐06 and 5.63E‐05 for gene‐based tests, respectively, after Bonferroni correction.

Results

The analysis sample contained 993 MCI cases and 3,509 cognitively normal participants; Table 1 contains the count for each race and sex subgroup. One significant (p‐value=1.06E‐7) single‐variant association (chr6:51712759:T:C in PKHD1) was detected in AA males (Figure 1). This variant had MAF=0.025 in AA males but was monomorphic in EA males. Four significant gene‐based associations with minor allele counts (MAC) ≥ 10 were discovered: CDC27 in AA females (SKAT‐O p‐value=6.63E‐07), C19orf18 in AA males (SKAT‐O p‐value=1.26E‐07), SLC16A10 in EA males and females combined (SKAT p‐value=1.90E‐06), and ZNF804A in EA females (T1 p‐value=2.69E‐07). Twenty‐three suggestive single‐variant and gene‐based associations with MAC ≥ 10 were identified (Figure 2).

Conclusions

MCI‐associated genes have diverse biological functions including cell division, sodium‐independent transportation of amino acids, and zinc finger binding. Our findings imply that the genetic underpinnings of MCI may differ by race and sex. External replication of our findings, as well as investigations using large samples in consortia, will provide insight into the pervasiveness of sex‐specific genetic effects in dementia‐related traits.
The Interaction between Ventricle to Brain Ratio and Serum Klotho on Cognition in Older Adults at Risk for Alzheimer’s Disease
Authors: Czaplicki Alec M , Gaitán Julian M. , Bendlin Barbara B , Johnson Sterling C. , Asthana Sanjay , Dubal Dena B. , Okonkwo Ozioma C.
Published: December 2021

Background

Ventricle to brain volume ratio (VBR) may be associated with Alzheimer’s disease (AD) progression and is a robust correlate of cognition in AD. Klotho is a circulating protein positively associated with cognition. The purpose of this study was to evaluate whether serum klotho attenuates the adverse effect of higher VBR on cognition in older adults at risk for AD.

Method

This study included 359 cognitively unimpaired participants from the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention (mean age = 61.8 ± 6.5, 67% female). VBR was calculated from structural T1 MRI scans as the ratio of total ventricle volume to the sum of grey and white matter. Fasting venipuncture was conducted and analyzed for serum klotho. Neuropsychological examination was conducted for global cognition (PACC3) and composite scores were calculated for executive function, immediate learning, and delayed recall. Linear regression models were performed to assess the effect of VBR on cognition, accounting for APOE, gender, age, and time difference between MRI and serum klotho measurements. Next, models were fitted with an interaction for VBR x klotho. Follow‐up analyses, stratified by median age (63.2 years), assessed age‐specific effects.

Result

Higher VBR predicted poorer delayed recall (β(SE)=‐6.3(3.1); p=.043), but not global cognition (β(SE)=‐4.9(3.0); p=.101), executive function (β(SE)=‐4.4(3.3); p=.178), or immediate learning (β(SE)=‐4.4(3.3); p=.185). Significant VBR x klotho interactions existed for global cognition (p=.024) and executive function (p=.009) whereby higher serum klotho attenuated the adverse effect of VBR. This effect was absent for immediate learning (p=.162) and delayed recall (p=.267). Among older participants, VBR predicted worse global cognition (β=‐7.4; p=.055), executive function (B=‐8.8; p=.048), and nearly delayed recall (β=‐8.1; p=.061), but not for immediate learning (p=.521). There were no effects among younger individuals (all p’s ≥ .203). Lastly, the VBR x klotho interaction on executive function was significant among older participants (p=.037).

Conclusion

Serum klotho may protect against the adverse effect of high VBR on cognition, particularly among older individuals.
Behavioural Effects of Aerial Parts of Alysicarpus glumaceus Vahl DC in Murine Models
Authors: Khan Ferhat , Abdulsalam Abdullateef , Saban Hafsat Abdullahi , Nazifi Abdullahi Balarabe , Sani Munir Ari , Shehu Aishatu , Olorukooba Amina Busola
Published: December 2021

Background

Alysicarpus glumaceus has been reported to be used in managing patients with neuropsychiatric disorders. This work aimed to determine the behavioural effects of aerial parts of Alysicarpus glumaceus in murine models.

Method

The behavioural effects of the drug extract was evaluated using elevated zero maze (EZM), stair case test (SCT) and the open field test (OFT) while beam walking was used to test for motor coordination deficit and stimulant activity in mice at doses of 500, 1000 and 1500 mg/kg using diazepam (0.05 mg/kg) as the standard and normal saline (NS) as the control.

Results

All the test doses of the extract reduced the stretch attend posture and head dips as well as the number of rearing without significant decrease in the number of stairs climbed in the EZM and SCT respectively when compared to NS. In the OFT, Alysicarpus glumaceus extract increased the number of square crossing but it was insignificant (p>0.05). The extract at 1000 and 1500 mg/kg significantly (p<0.01) decreased the number of rearing; while at 500 mg/kg it significantly (p<0.001) decreased the number of rearing. At all the test doses used, there was no significant difference in time to reach the goal box and number of foot slips, however, mice given 500 mg/kg of the extract produced a significant (p<0.05) increase in time spent on the beam.

Conclusion

The findings revealed that the aerial parts of Alysicarpus glumaceus possesses central nervous system depressant actions.
Improving Cancer Detection and Treatment by pH‐Sensitive Peptide Nanoparticle Drug Delivery Platform: Pharmacokinetics, Toxicity, and Immunogenicity Profile
Authors: Choi Hoon , Cao Jianbo , Qiao Hui , Chen I-Wei , Zhou Rong
Published: December 2021

It was previously reported that a nanoparticle made of ultra pH‐sensitive peptides (pH‐NP) undergoes self‐dissolution in moderately acidic (pH ≤ 6.9) condition that mimics the pH in extracellular tumor environment, leading to release of drug cargo molecules. Herein, it is demonstrated that this peptide‐based nanodelivery platform can be used to formulate poorly water‐soluble small molecules to improve cancer diagnosis and treatment. Indocyanine green (ICG) encapsulated in pH‐NP (ICG‐pH‐NP) significantly increases tumor‐specific accumulation compared with “free” ICG, leading to excellent in vivo optical imaging contrast. An investigational cancer drug, OTS964, formulated in pH‐NP (OTS‐pH‐NP), sensitizes the drug‐resistant triple‐negative breast cancer to chemotherapy (paclitaxel), resulting in a remarkable tumor regression, whereas OTS964 in standard formulation does not (P = 0.0004). The potential immunogenicity and bone marrow toxicity of this nanoparticle are further investigated by administering drug‐free pH‐NP at nanoparticle dose regimens, representing 1.5× and 4.5×, respectively, of which are used in the treatment (OTS‐pH‐NP) study. The data show that the pH‐NP is not immunogenic and is well‐tolerated. Taken together, self‐dissolution and the release of drug cargo in response to the tumor's acidic extracellular pH faciliates drug delivery when mediated by the pH‐NP nano platform, making it a promising, clinical translational delivery platform for enhancing cancer detection and treatment.
Unveiling Center‐Type Topological Defects on Rosettes of Lead Zirconate Titanate Associated to Oxygen Vacancies
Authors: Neckel Itamar T. , da Silva Francisco M. C. , Guedes Eduardo B. , Dias Carlos S. B. , Soares Marcio M. , Costa Carlos A. R. , Mori Thiago J. A. , Björling Alexander , Zakharov Alexei , Tolentino Helio C. N.
Published: December 2021

Understanding the formation of topological defects in ferroelectric materials can provide access to their unusual physics, invaluable for possible applications of domain engineering in nanoelectronics. The present study shows the spontaneous formation of center‐type topological defects in lead zirconate titanate (PZT) films, characterized by a strong in‐plane radial electromechanical response on rosette‐like structures, as revealed by piezoelectric response force microscopy. Multi‐modal electron and X‐ray based techniques provide a comprehensive set of tools for delving at atomic scale the local chemistry, electronic, and crystalline structures. The elemental surface‐sensitivity of soft X‐ray absorption shows chemical segregation and drastic changes in the titanium electronic structure, which have been associated to oxygen vacancies, leading to a mechanism that describe the polarization symmetry on the rosettes. X‐ray nanofluorescence experiments revealed titanium segregation, corroborating with the absorption and low energy electron microscopy images. Taking advantage of a nanobeam, 2D nanodiffraction maps probed the complex microstructure of the domains, revealing its mosaicity and lattice strain at the nanoscale. This study highlights a complex topological structure and provides, by the simultaneous application of a set of analytical tools, a broad comprehension of the formation of center‐type ferroelectric topological defects in PZT.
Cation‐Tuning Induced d‐Band Center Modulation on Co‐Based Spinel Oxide for Oxygen Reduction/Evolution Reaction
Authors: Wang Zepan , Huang Jiahui , Wang Ling , Liu Yangyang , Liu Wenhui , Zhao Shenlong , Liu Zhao‐Qing
Published: December 2021

Atomic substitutions at the tetrahedral site (ATd) could theoretically achieve an efficient optimization of the charge at the octahedral site (BOh) through the ATd‐O‐BOh interactions in the spinel oxides (AB2O4). Despite substantial progress having been made, the precise control and adjustment of the spinel oxides are still challenging owing to the complexity of their crystal structure. In this work, we demonstrate a simple solvent method to tailor the structures of spinel oxides and use the spinel oxide composites (ACo2O4/NCNTs, A=Mn, Co, Ni, Cu, Zn) for oxygen electrocatalysis. The optimized MnCo2O4/NCNTs exhibit high activity and excellent durability for oxygen reduction/evolution reactions. Remarkably, the rechargeable liquid Zn–air battery equipped with a MnCo2O4/NCNTs cathode affords a specific capacity of 827 mAh gZn−1 with a high power density of 74.63 mW cm−2 and no voltage degradation after 300 cycles at a high charging–discharging rate (5 mA cm−2). The density functional theory (DFT) calculations reveal that the substitution could regulate the ratio of Co3+/Co2+ and thereby lead to the modulation of the electronic structure accompanied with the movement of the d‐band center. The tetrahedral and octahedral sites interact through the Mn−O−Co, and the Co3+Oh of MnCo2O4 with the optimal charge structure allows a more suitable binding interaction between the active center and the oxygenated species, resulting in superior oxygen electrocatalytic performance.
Improving some structural and biological characteristics of bacterial cellulose by cross‐linking
Authors: Geravand Sahar Abbasi , Khajavi Ramin , Rahimi Mohammad Karim , Ghiyasvand Manouchehr Shamsini , Meftahi Amin
Published: December 2021

Bacterial cellulose (BC) has received attention in research because of its unique characteristics. Especially, it has emerged as a very promising and versatile candidate for biomedical applications. In this study, it was aimed to boost some structural and biological properties of BC by crosslinking, which play important role in medical field. Synthesized, purified, and neutralized BC pellicles were cross‐linked (X‐linked) in different concentrations (5, 10, and 20 wt/vol%) with citric acid/sodium hypophosphite. Formation of X‐Links confirmed by Fourier transform‐infrared. Obtained spectrums showed that the density of X‐links would raise up to a limit with increasing the concentration of citric acid. X‐ray diffraction data analysis of samples showed a decline in crystallinity of samples with increasing the intensity of X‐linking treatment. Scanning electron microscope images and MTT assay confirmed the better cell adhesion, viability and proliferation for X‐linked samples and no toxicity was observed for all samples including (non‐X‐linked and X‐linked). It was concluded that some important structural and biological properties of BC (which were very critical for biomedical applications) were related mutually and could be modified with X‐linking treatment simultaneously.