bluuebunny/crossref_metadata_2025 huggingface dataset:
Multifunctional all‐polymer photovoltaic blend with simultaneously improved efficiency (18.04%), stability and mechanical durability
Authors: Liu Tao , Zhou Kangkang , Ma Ruijie , Zhang Libin , Huang Ciyuan , Luo Zhenghui , Zhu Hongxiang , Yao Shangfei , Yang Chuluo , Zou Bingsuo , Ye Long
Published: December 2022

One of the most appealing material systems for solar energy conversion is all‐polymer blend. Presently, the three key merits (power conversion efficiency, operation stability and mechanical robustness) exhibited a trade‐off in a particular all‐polymer blend system, which greatly limit its commercial application. Diverting the classic ternary tactic of organic solar cells based on polymer, nonfullerene small molecule and fullerene, herein we demonstrate that the three merits of a benchmark all‐polymer blend PM6:PY‐IT can be simultaneously maximized via the introduction of a polymerized fullerene derivative PPCBMB. Importantly, the addition of the guest component promoted the power conversion efficiency of PM6:PY‐IT blend from 16.59% to 18.04%. Meanwhile, the device stability and film ductility are also improved due to the addition of this polymerized fullerene material. Morphology and device physics analyses reveal that optimal ternary system contains well‐maintained molecular packing and crystallinity, being beneficial to keeping favorable charge transport and the reduced domain size contributed to charge generation and ductility improvement. Furthermore, the ternary photovoltaic blend was successfully used as photocatalysts, and an excellent heavy metal removal from water was demonstrated. This study showcases the multi‐functions of all‐polymer blends via the use of polymerized fullerenes.
Methodological gaps in clinical dementia research
Authors: Boccardi Marina
Published: December 2022

Background

Evidence‐based decisions allow to compile clinical guidelines, or to approve or refund new treatments or diagnostic procedures. Different evidence‐to‐decision (EtD) procedures exist to define recommendations based on evidence. However, often data are not eligible to such EtDs due to faults in the methodology that generated them. This is a relevant and upstream problem hurdling the transfer of knowledge. Aim of this work is to outline these methodological problems to help overcoming such concrete hurdle to knowledge transfer.

Method

A range of methodological issues hampering eligibility of data to EtD was searched across different evidence assessment initiatives, based on the methodological requirements defined by the main steps of formal methodologies for the validation of diagnostic biomarkers, namely analytical validity, clinical validity, and clinical utility.

Result

Methodological gaps involve all these main development phases. The main issues at the analytical validity phase consist in limited use of standard operating procedures. This causes exceedingly large variability of data that cannot be amended post hoc. Such variability thus propagates to all downstream validation studies and final data cannot support any decision, not in favor nor against clinical recommendations. At the phase of clinical utility, many studies do not use either proper gold‐ or reference‐standards, or study designs able to address the target question. At the clinical utility phase, implementation methods are still not systematically imported and adapted to the dementia field, and the assessed outcomes are mainly defined by researchers, with limited participation of other relevant stakeholders (e.g., regulators; patients or caregivers).

Conclusion

With such gaps along the translational continuum, published data cannot support evidence‐based decision‐making. To improve implementation, attention should not only target the latest adoption steps, but many more upstream steps that eventually prevent the formal approval and refund of new diagnostic procedures or of other innovation.
Network‐level permutation entropy of resting‐state MEG recordings: a novel biomarker for early‐stage Alzheimer’s disease?
Authors: Scheijbeler Elliz P. , van Nifterick Anne M , Stam Cornelis J , Arjan Hillebrand , Gouw Alida A , de Haan Willem
Published: December 2022

Background

Increasing evidence suggests that measures of signal variability and complexity could present promising biomarkers for Alzheimer’s disease (AD). Earlier studies have however been limited to the characterization of local activity. Here, we investigate whether a network version of permutation entropy could serve as a novel biomarker for early‐stage AD.

Method

Resting‐state source‐space magnetoencephalography was recorded in 18 subjects with subjective cognitive decline (‘SCD’) and 18 subjects with mild cognitive impairment (‘MCI’). Local activity was characterized by permutation entropy (PE). Network level interactions were studied using the inverted Joint Permutation Entropy (JPEinv), corrected for volume conduction. Entropy of the overall network across different temporal scales was quantified using a global permutation entropy measure.

Result

The JPEinv showed a reduction of nonlinear connectivity in MCI subjects in the theta and alpha band. Local PE showed increased theta‐band entropy. Between‐group differences were widespread across brain regions. ROC analysis of classification of MCI versus SCD subjects revealed that a linear regression model trained on JPEinv features (78.4% [62.5‐93.3%]) slightly outperformed PE (76.9% [60.3‐93.4%]) and relative theta power based models (76.9% [60.4‐93.3%]). The global entropy measure is currently being optimized. Results will be available at a later stage.

Conclusion

Classification performance of theta JPEinv was at least as good as the relative theta power benchmark. The JPEinv is therefore a potential biomarker for early‐stage AD and should be explored in larger studies.
Harmonization of neuropathology measures and characterization of neuropathological burden across population‐based autopsy samples
Authors: Nichols Emma , Merrick Richard , Wharton Stephen , Matthews Fiona E , Brayne Carol , Vos Theo
Published: December 2022

Background

Most autopsy samples are based on clinical cohorts or case series; the distribution of neuropathologies may be biased in these samples compared to the general population. A small number of population‐based neuropathology cohorts address these concerns but are often limited by small sample sizes and restrictions to specific geographic locations or groups. Harmonization would allow comparisons across settings and increases in precision of estimates.

Method

We leveraged data from the Religious Orders Study and Memory and Aging Project (N=1882), the Adult Changes in Thought study (N=721), the Cognitive Function and Ageing Studies (N=444), and the Cambridge City over‐75s Cohort Study (N=241). First, we identified measures in common across cohorts or a subset of cohorts and documented protocol differences. We characterized distributions of pathologies by age group (80‐89 vs. 90+) and quantified correlations between pathologies using polychoric correlations. We described overlap between pathologies for five key measures (CERAD neuritic plaques, Braak stage, macro‐ and micro‐infarcts, and Lewy body disease).

Result

We harmonized measures of 10 pathologies available in at least 3/4 studies (7 across all studies). Distributions of Alzheimer’s disease (AD) pathologies (CERAD neuritic plaques, Braak stage) varied less across cohorts (Range [Severe CERAD]=33%); Range [Braak stage V‐VI]=22%) than distributions of vascular disease pathology such as atherosclerosis (Range [Moderate‐Severe Atherosclerosis]=51%). After meta‐analyzing correlations across studies, we found strong correlations between AD pathological features (r=0.70,p<0.001: Braak stage and CERAD neuritic plaque score) and moderate correlations between vascular features (e.g. r=0.34,p<0.001: macro‐ and micro‐infarcts). There was also evidence of small correlations between AD features and other neuropathology measures (r=0.21,p<0.001: CERAD neuritic plaque score and hippocampal sclerosis). Pooling data across cohorts, out of five key measures, 69% of the sample had two or more co‐occuring pathologies (2=39%, 3=23%, 4=6%, 5=1%).

Conclusion

Harmonization and data pooling was feasible across a range of measures; however, we found that measures of AD pathology appear more standardized. Higher variability in vascular measures may partly reflect a lack of standardized criteria for quantification. Strong correlations and frequent co‐occurrence between measures highlights the complexity and multi‐morbidity of the brain pathologies thought to underlie dementia in older adults.
Associations of ischemic heart disease with dementia and cognitive decline in older adults: Results from a 12‐year population‐based cohort study
Authors: Imahori Yume , Wu Jing , Ljungman Petter , Vetrano Davide Liborio , Laukka Erika J , Grande Giulia , Fratiglioni Laura , Qiu Chengxuan
Published: December 2022

Background

Ischemic heart disease (IHD) is a leading cause of death worldwide and a potential risk factor for dementia. However, the association of IHD with dementia and cognitive decline in old age has not been extensively addressed in population‐based cohorts. Furthermore, the extent to which the potential association of IHD with cognitive decline might be attributable to common complications of IHD, such as heart failure (HF) and atrial fibrillation (AF), remains unclear. The objective of this study is to investigate the longitudinal association of IHD with dementia and cognitive decline, and to clarify the role of HF and AF.

Method

We analysed data from 2615 dementia‐free participants in the population‐based Swedish National study on Aging and Care in Kungsholmen (age ≥ 60years, female 62%). Participants were regularly followed from 2001‐2004 (baseline) through 2013‐2016. IHD, HF, and AF cases until baseline were identified through patient registers, physical and instrumental examinations, and interviews by physicians. Dementia was diagnosed according to the DSM‐IV criteria. Global cognitive function was assessed with a neuropsychological test battery.

The associations of IHD with incident dementia and cognitive decline were investigated using Cox proportional hazard models and linear mixed‐effects models, respectively. The models were controlled for age, sex, education, smoking, alcohol consumption, physical activity, vascular risk factors, and concomitant cardiovasulcar diseases (AF, HF, and stroke). Furthermore, we performed the stratified analysis by the presence of AF or HF.

Result

During the 12‐year follow‐up period, 400 participants (15%) developed dementia. The multi‐adusted hazard ratio (HR) of dementia associated with prevalent IHD was 1.34 (95% CI: 1.03, 1.75) compared to those without IHD. This association remained significant in IHD without prevalent AF or HF at baseline. Similarly, prevalent IHD was associated with an average annual change in global cognitive z‐score of ‐0.02 (95% CI: ‐0.03, ‐0.01). The associations remained significant after excluding individuals with AF and HF. There was no statistical interaction of IHD with age, sex, or APOE genotype on risk of dementia and cognitive decline.

Conclusion

IHD is a risk factor for dementia and cognitive decline in the general older population independent of HF and AF.
Associations between semantic memory for proper names in story recall and CSF amyloid and tau in a cognitively unimpaired sample
Authors: Hale Madeline R , Koscik Rebecca Langhough , Du Lianlian , Hermann Bruce P , Van Hulle Carol A. , Suridjan Ivonne , Kollmorgen Gwendlyn , Basche Kristin E , Bruno Davide , Sanson‐Miles Leah , Jonaitis Erin M. , Chin Nathaniel A. , Okonkwo Ozioma C. , Bendlin Barbara B. , Carlsson Cynthia M. , Zetterberg Henrik , Blennow Kaj , Betthauser Tobey J , Johnson Sterling C. , Mueller Kimberly D
Published: December 2022

Background

Difficulty recalling proper names (PNs; e.g., names of people/places) is a common complaint of individuals at risk for Alzheimer’s disease (AD). We recently reported that cognitively unimpaired (CU), positron emission tomography amyloid‐beta (Aβ) positive (A+) individuals recalled fewer PNs than Aβ negative individuals on the Logical Memory (LM) delayed story recall test. Declines in delayed LM total scores (LMtot) have been associated with cerebrospinal fluid (CSF) A+ and tau (T); the relationship between PNs and AD‐CSF biomarkers is unknown. We investigated whether delayed recall of PNs at baseline, or most recent visit, were associated with biomarker positivity for two AD‐CSF biomarkers, and whether PNs were more strongly associated than traditionally used LMtot scores.

Method

CU participants with no other neurological diagnoses and CSF data available were included from the Wisconsin Registry for Alzheimer’s Prevention (N = 219; mean baseline age [standard deviation] = 58.12 [6.31]). Item‐level LM data were used to create PNs (0–9) and LMtot (0–50) scores. A and T statuses (+/‐) were determined using published cutoffs for CSF Aβ42/40 and phosphorylated tau 181 (pTau181). Logistic regression models investigated whether LMtot or PNs were associated with most recent biomarker status, covarying CSF age, sex, Wide Range Achievement Test‐3 score, and apolipoprotein E4 status. Model fits were compared using Akaike information criterion (AIC). For descriptive purposes, effect sizes between adjusted means of PNs and LMtot were calculated for biomarker‐positive vs. negative groups.

Result

Overall, 31 individuals (14%) were Aβ42/40+ and 29 (13.0%) were pTau181+ (Table 1). Baseline PNs nor LMtot were not significantly associated with AD‐CSF biomarkers (Table 2). Most recent PNs and LMtot were associated with AD‐CSF (Table 3). AICs indicated similar fits between PNs and LMtot at each timepoint, and better fits with most recent vs. baseline LM scores. Effect sizes were higher for most recent LM metrics compared to baseline and were slightly higher for PNs than LMTot for Aβ (Figure 1).

Conclusion

Metrics from story recall tasks are associated with increased risk of CSF‐AD biomarker positivity and suggest that PNs from story recall may be sensitive to early AD biomarker changes. Validation by replication in additional cohorts is required.
Immunoneurology; targeting the brain Immune system as a novel therapeutic strategy for dementia and neurodegeneration
Authors: Rosenthal Arnon
Published: December 2022

Immuno‐neurology: targeting the brain Immune system as a novel therapeutic strategy for dementia and neurodegeneration

For the last two decades, the predominant approach to treating neurodegenerative disorders was to remove or disaggregate disease‐typifying, misfolded proteins or prevent their synthesis. Multiple clinical trials with drugs that counteract beta‐amyloid or Tau protein in Alzheimer’s disease (AD), Alpha‐Synuclein in Parkinson’s disease, SOD1, C9orf72, and TDP‐43 in ALS, and the Htt protein in Huntington’s disease, are still in progress. An alternative broad‐based therapeutic strategy for degenerative brain disorders is to recruit the brain’s immune system to thwart multiple disease pathologies. This approach, designated immuno‐neurology, is conceptually akin to immuno‐oncology, which revolutionized cancer therapy by recruiting the immune system to counteract tumor growth. Immuno‐neurology hypothesizes that impaired activities of microglia the innate immune cells of the brain, due to normal aging or genetic mutations cause havoc in our brain’s ability to function and deal with insults and thus enable neurodegeneration. The scientific rationale for immuno‐neurology is derived from our growing understanding of the role human genetics and microglia play in the etiology of brain disorders. Human genetics revealed that while AD is characterized by synaptic and neuronal loss, many genetic variations that increase the risk to develop AD reside in genes that are specifically expressed in, and control the survival and function of, microglia. Microglia are now known to be key regulators of brain well‐being. They are responsible for the removal of misfolded proteins, myelin debris, and disease‐causing agents as well as the repair of leaky blood vessels and injured brain tissue. In addition, microglia, directly and indirectly, regulate brain function by controlling the number of synaptic connections and the survival or activity of oligodendrocytes, astrocytes, and endothelial cells. Using familial risk genes that regulate microglia, such as Progranulin, TREM2, CD33, and MS4A, as levers to repair and harness these critical brain immune cells has emerged as a promising therapeutic strategy for degenerative brain disorders.
Examining I‐CONECT Intervention Effect on Psychosocial Wellbeing
Authors: Yu Kexin , Hampstead Benjamin M. , Wild Katherine , Silbert Lisa C , Dodge Hiroko H
Published: December 2022

Background

The Internet‐based Conversational Engagement Clinical Trial (I‐CONECT, ClinicalTrials.gov:NCT02871921) intervention provided interpersonal interactions with video calls to socially isolated older adults. It is hypothesized that such intervention could improve individuals' psychosocial wellbeing by increasing social contacts. This abstract examines I‐CONECT intervention effects on psychological wellbeing outcomes.

Method

The intervention group received 30‐minute video chats 4 times/week for 6 months followed by 2 times/week for additional 6 months. The control group received weekly check‐in calls for 12 months. We used data from the baseline, six‐month and twelve‐month follow‐ups. Psychosocial outcomes were measured with NIH Toolbox Emotional Battery (NIHTB‐EB). Three domain scores, negative affect, social satisfaction, and psychological wellbeing, were calculated with 17 subscale scores weighted by factor loading. Mixed Models for Repeated Measures (MMRM) were run for the three psychosocial outcomes, controlling for age, sex, education, and experience of COVID‐19 pandemic. Participants were considered affected by COVID‐19 if any of the data points were collected after March 2020. Subsample analyses were conducted by participants' cognitive status (with normal cognition vs. MCI).

Result

The analysis included 134 participants, 70 with normal cognition and 64 with MCI. The sample’s mean age was 82.3, 44.9% were in the intervention group, 67.0% were female, the average year of education was 15.1, and 51.6% were affected by the pandemic. For the subsamples of individuals of normal cognition and MCI, we did not find any significant change in psychosocial outcomes due to the intervention. However, both intervention and control groups increased social satisfaction scores at both 6‐month and 12‐month (Table 1, Figure 1), suggesting that weekly phone check‐ins and frequent video‐chats interactions can provide the same magnitude of improvement in psychosocial wellbeing. We observed the COVID‐19 pandemic affected social satisfaction of both intervention and control groups negatively for those with MCI but did not affect the individuals with normal cognition.

Conclusion

Both intervention and control groups improved in a measure of social satisfaction. Once per week 10‐minutes phone check‐ins provided for the control group seemed to be sufficient for improving social wellbeing. Implementing weekly phone check‐ins in the community might help improve psychological wellbeing among socially isolated older adults.
I‐CONECT: Efficacy in Primary and Secondary outcomes
Authors: Dodge Hiroko H , Wu Chao‐Yi , Albin Roger L. , Hampstead Benjamin M. , Kaye Jeffrey A , Wild Katherine , Silbert Lisa C
Published: December 2022

Background

Octogenarians are the fastest growing segment of the population worldwide, but are often excluded from pharmacological intervention trials. Slowing cognitive decline and delaying the onset of dementia even for a few years among this age group could reduce prevalent dementia significantly. Behavioral intervention targeting the older old, which can be easily started and sustained even among the homebound, is needed.

Method

Based on the epidemiological findings and promising results in our previous pilot project, we developed Internet‐based Conversational‐Engagement Clinical Trial (I‐CONECT)” (ClinicalTrial.gov: NCT02871921). I‐CONECT is a multi‐site, assessor‐blind, randomized controlled behavioral intervention trial intended to enhance cognitive reserve by increasing social interactions, specifically conversational interactions, using video conferencing. Through community outreach and mass‐mailing, 29,664 contacts were attempted, resulting in 1,139 telephone screenings. Ultimately 186 socially isolated participants aged 75 and older (mild cognitive impairment (MCI) or normal cognition (NC)) were randomized (mean age = 81.1, 20% African Americans). The experimental group engaged in 30‐minute video chats 4 times per week for 6 months, followed by twice per week for an additional 6 months, and weekly 10‐minute phone check‐ins. The control group received only the weekly phone check‐ins. Due to the COVID‐19 pandemic, we replaced in‐home assessments with telephone assessments (T‐COG) during the intervention. Accordingly, we conducted two separate analyses: one using only those who completed Month 6 assessments before the COVID pandemic (n = 56, N56Analysis) and another using all randomized participants (n = 186, N186Analysis) with the latter analysis controlling for COVID‐19 pandemic exposure using mixed models for repeated measures.

Result

Among MCI participants, global cognition as measured by the Montreal Cognitive Assessment (MoCA) (primary outcome) was 1.76 points higher at Month 6 assessments among the experimental group compared with the control group (M56analysis) (p = 0.03, Cohen’s d = 0.73). At Month 12, we also observed 2.19 points higher score (p = 0.03) in Craft Story Immediate Recall (episodic memory/encoding, secondary outcome) in M186Analysis.

Conclusion

Despite the reduced sample size, we demonstrated efficacy in our primary and secondary outcomes and feasibility of executing methods to enhanced social engagement in isolated older adults using a virtual platform. Long term effects of this intervention will be examined in a future Phase III trial.
Plasma biomarkers combined with UPDRS and MoCA for differential assessments of amnestic cognitive impairment (aMCI), Parkinson’s disease (PD+PDD) and dementia with Lewy body (DLB): A pilot study
Authors: Sabbagh Marwan N. , Lue LihFen , Decourt Boris , Shill Holly
Published: December 2022

Background

There would be tremendous value for having biomarker panels as screening tools for the assessment of AD and PD pathologies. Technologies that increase the sensitivity and accuracy of the measurement of plasma Aβ42, total Tau (t‐Tau), phosphorylated Tau (P‐tau),) have emerged and there is interest in testing plasm alpha synuclein (α‐syn). The specific aim of the present study was to assess the accuracy of plasma Aβ42, total Tau (t‐Tau), and α‐syn combined with clinical measures in identifying mild cognitive impaired (MCI), PD/PDD, and DLB cases.

Methods

The total sample size was 77 subjects including 37 NC, 16 MCI [NIA‐AA Criteria, Alberts 2011], 12PD/PDD [Hughes criteria] and 12 DLB [McKeith criteria]. NC subjects reported no demonstrable cognitive complaints, were intact functionally and cognitively.. The variables included age, education, MOCA, UPDRS, and H‐Y stage. Plasma biomarkers were assayed by ImmunoMagnetic Reduction (IMR) technology (MagQu, Inc).

Results

MOCA scores were lower in the aMCI and DLB groups. The UPDRS and H‐Y stage scores were significantly higher in the PD and DLB groups. The sensitivities using biomarkers (abeta42xT‐Tau) or MoCA individually to discriminate aMCI from NC are 0.625 to 0.92, respectively. The combination of biomarker and MoCA shows the 0.929 for the sensitivity. As to the specificity, individual biomarker or MoCA shows 0.778, whereas the combination of biomarker and MoCA shows 0.833. .When clinical measures were combined with biomarker values (UPDRS w/alpha‐syn; DLB status could be differentiated from PD/PDD with a sensitivity 0.955, Specificity 0 980, The combination of p‐tau181 with UPDRS had a sensitivity of 0.833 and specificity of 0.833 which was better than the sensitivity and specificity of the individual measures.

Conclusions

Investigations on the discrimination of DLB vs. PDD are rare. In this pilot study, we show that IMR assays of plasma α‐Syn, P‐tau 181, and Aβ42 x t‐tau in combination with clinical measures (UPDRS and MOCA), could differentiate PD/PDD from DLB, as well as NC from aMCI. Thus, our data suggest clinical utility of these novel biomarker modalities and panels. Differentiating DLB from PDD could be consequential in clinical characterization. Future studies will aim to replicate our findings on larger group sizes.
Circulating neurodegeneration biomarkers neurofilament light protein and p‐tau181 are increased in individuals with heart failure at risk for vascular cognitive impairment
Authors: Hoyer‐Kimura Christina , Konhilas John , Sweitzer Nancy , Ryan Lee , Hay Meredith
Published: December 2022

Background

Systemic inflammation, which is present in heart failure (HF), is known to increase risk for dementia and development of vascular cognitive impairment and dementia (VCID). Both neurofilament light protein (NfL) and tau phosphorylated at threonine‐181 (p‐tau181) are well known biomarkers of neurodegeneration in both Alzheimer’s disease and non‐Alzheimer’s disease neurodegenerative diseases. The purpose of the present study was to determine if blood levels of NfL and p‐tau181 are increased in HF patients at risk for VCID.

Method

We performed a retrospective study of 58 participants from the previously completed TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). TOPCAT participants had symptomatic HF categorized using New York Heart Association (NYHA) criteria, were > 50 years of age, and had ejection fraction (LVEF) ≥45%, assessed within 6 months from study start (n=58, 52% female). Control serum samples were obtained from age‐matched adults between 50‐85 with no known health issues (n=24, 50% female). NfL was measured using Simoa Quanterix and p‐Tau181 measured with SimoaHuman pTau‐181 V2 kit. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post.

Result

Baseline NfL levels were significantly higher in NYHA class I/II (n=56) and III/IV (n=54, p<.0001) than measured in age‐matched controls (see table for values). Over 12‐months follow‐up, participants in NYHA class I/II had an increase in NfL of 9.6±5% relative to baseline and those in class III/IV had a 31.7±17% increase from baseline. P‐tau181 levels were also significantly higher in both NYHA class I/II (n=56) and III/IV (n=54, p=.0002) as compared to age‐matched controls (see table for values) with levels were significantly higher in class III/IV than in class I/II participants (ANOVA, Dunnett’s post, p<.001). Levels of p‐tau181 did not show significant changes over the 12‐month time in any group.

Conclusion

These results demonstrate that 2 well‐studied biomarkers of neurodegeneration, NfL and p‐tau181, are elevated in subjects with HF. Studies are underway to determine if biomarker levels correlate with measures of cognitive function and MRI measures of brain structure and function in HF patients. (Supported by NIA U01AG066623).
Novel advances in the characterization of dementia subtypes: from multi‐feature classification to whole brain computational models
Authors: Prado Pavel , Moguilner Sebastian , Herzog Ruben A , Parra‐Rodriguez Mario A , Otero Monica , Mejía Jhony Alejadro , Sainz Agustín , Taglizucchi Enzo , Ibáñez Agustin
Published: December 2022

Background

Brain functional connectivity analyses derived from electroencephalography (EEG) provides relevant information for classification of dementia subtypes. The predictive strength of classification tools can be benefit from integrative, multi‐feature analysis of EEG which result in composite metric of functional connectivity. Additionally, significant improvement can be obtained when connectivity analyses consider the dependence between groups of regions as a whole system (high order interactions), instead of conceiving the network as a collection of pairwise interactions.

Method

Five minutes, resting‐state EEG (rsEEG) was recorded from healthy controls (HC, n=42), and participants diagnosed with either behavioral variant frontotemporal dementia (bvFTD, n=19) or Alzheimer Disease (AD, n=33). EEG source localization analyses were conducted. Whole brain functional connectivity (82 anatomic compartments, AAL atlas) was analyzed using 17 metrics to capture different statistical dependence between source space rsEEG time series, in both time‐, and frequency‐domains. Furthermore, high‐order, non‐lineal statistical interdependencies between group of brain regions were assessed using multivariate information theory. Gradient boosting classifiers with Bayesian optimization, harmonization, and feature elimination were implemented.

Result

Classification of dementia subtypes, using a particular frequency‐domain connectivity metric, displayed better performances as features for classification comprised information from multiple EEG frequency bands. Likewise, classification systems including information from several connectivity metrics outperformed those achieved with individual metrics. Dementia classification conducted with connectivity metrics derived from mutual information significantly improved as order of interaction (number of brain regions consider as a network) increased. This latter approach boosted multimodal (fMRI‐EEG) classification of dementias based on brain functional connectivity, and served as input for whole‐brain computational models describing the pathophysiology of neurodegenerative diseases.

Conclusion

Integrative, composite metrics of connectivity, and connectivity analyses of source localized rsEEG based in high order interactions capture relevant information to discriminate dementia subtypes, and provide a reliable and interpretable description of brain functional connectivity and neurodegeneration.
The Need for Big Data and Large Consortiums on The Use of EEG as a Potential Tool to Decide on Which Frequency We Should Use for Sensory Entrainment in Alzheimer’s Disease?
Authors: Güntekin Bahar , Duygun Rümeysa , Bölükbaş Burcu , Yener Görsev , Erdal Furkan
Published: December 2022

Background

Successful use of sensory 40 Hz‐gamma entrainment has been shown in Alzheimer’s Disease animal models. Few studies had used 40 Hz‐gamma sensory gamma entrainment on human subjects and there are contradictory results on these studies. We think there could be different frequency dynamics in animals and in humans. To answer this question, we aimed to analyze the dominant gamma frequency band in Alzheimer’s Disease patients, healthy young and elderly subjects. We hypothesized that the dominant gamma frequency would be different across groups being lower in AD patients.

Method

Eyes open and eyes closed spontaneous EEG data of 179 participants ( 59 early‐stage AD patients, 60 healthy elderly, and 60 healthy young subjects) were analyzed. Fast Fourier Transform (FFT) was applied to eyes open and eyes closed data separately. The three highest peaks of power value as the gamma dominant peak frequency were analyzed.

Results

The results indicated that the gamma dominant peak frequency of AD patients (Mean eyes opened = 33.4 Hz, Mean eyes closed = 32.7 Hz) was lower than healthy elderly (Mean eyes opened = 35.5 Hz, Mean eyes closed = 35.0 Hz) and healthy young subjects (Mean eyes opened = 37.2 Hz, Mean eyes closed = 37.0 Hz) (p< 0,05). Furthermore, the healthy elderly group had lower gamma dominant peak frequency values than the young healthy group (p< 0,05).

Conclusion

The results of the present study showed that the dominant gamma frequencies are being slower as the age increase, moreover it is even getting slower in AD patients. The dominant gamma frequency of healthy elderly age is 35 Hz for eyes closed and 35.5 Hz for eyes‐open conditions. Since the AD patients had a 32.7‐33 Hz gamma frequency range it would be adequate to use 35 Hz gamma entrainment as the dominant frequency of the healthy elderly group to normalize the slower gamma frequency band in AD patients. So rather than 40 Hz, gamma entrainment 35 Hz gamma entrainment could be more beneficial for AD subjects. To test this hypothesis, a global consortium is needed to find out the right gamma frequency in large subject groups.
Financial Altruism is Associated with Alzheimer’s Disease Neurocognitive Profile in Older Adults
Authors: Weissberger Gali H , Samek Anya , Mosqueda Laura , Nguyen Annie , Lim Aaron , Fenton Laura E. , Han Duke
Published: December 2022

Background

Older age is associated with an increase in altruistic behaviors such as charitable giving. The present study aimed to investigate the cognitive correlates of financial altruism in older adults.

Method

Older adults (N = 67; M age = 69.21, SD = 11.23; M education years = 15.97, SD = 2.51; 58.2% female; 71.6% Non‐Hispanic White) completed a comprehensive neuropsychological assessment and an altruistic choice paradigm in which they made decisions about allocating money between themselves and an anonymous person.

Result

In multiple linear regression analyses that controlled for age, education, and sex, financial altruism was negatively associated with performance on cognitive measures typically sensitive to early Alzheimer’s Disease (including word list learning and recall, delayed story recall, and animal fluency). When financial altruism responses were grouped, differences between altruistic groups revealed that individuals who gave more than they kept for themselves demonstrated the worst cognitive performance compared to those who gave equally (kept half and gave half) and those who gave less (kept more and gave less).

Conclusion

Findings of this study point to a negative relationship between financial altruism and cognitive functioning in older adults on measures known to be sensitive to Alzheimer’s Disease (AD). Findings also point to a potential link between financial exploitation risk and AD in older age.
Use Acetazolamide in the Complex Therapy of Alzheimer’s Disease
Authors: Sushko Viktor Vasilievich , Sushko Viacheslav Viktorovich
Published: December 2022

Background

Impaired glymphatic clearance is one of the causes of Alzheimer’s disease. Acetazolamide is a drug that affects the normalization of glymphatic clearance.

Methods

We followed four women aged 65‐70 years with a diagnosis of Alzheimer’s disease in 2019‐2021. They were treated in the unit according to Alzheimer’s disease treatment standards. During periodic examination by an ophthalmologist, they were diagnosed with first‐stage glaucoma (initial) ‐ a blind spot interfering with normal peripheral vision and a deepening of the optic disc in the central zone were identified. For a glaucoma treatment, they were prescribed Acetazolamide 125 mg once a day in the morning for 7 days with weekly monitoring of intraocular pressure. They also received Asparkam, 1 tablet, 3 times a day during Acetazolamide administration to prevent a deficiency of potassium ions in the body. On days 12‐14 after normalization intraocular pressure, Acetazolamide administration was discontinued. To monitor the dynamics of cognitive impairment, patients on the unit underwent Trail Making Test Parts A & B paper‐pencil versions every month.

Results

Before glaucoma treatment, the patients' Trail Making Test Parts A speeds were 84, 87, 90, and 92 seconds. The speed of Part B was 270, 300, 293, and 305 seconds. After two weeks of glaucoma treatment, patients again completed the Trail Making Test Parts A & B paper‐pencil versions. The patients' speeds for Part A were 60, 68, 63, and 70 seconds. The speeds in Part B were 180, 190, 217, and 194 seconds.

Conclusion

Administration of Acetazolamide has a positive effect on patients with cognitive deficits and can be successfully used as part of the complex therapy of Alzheimer’s disease.
Early lysosome defects precede neurodegeneration with Aβ and tau aggregation
Authors: Lee Eugene , Miller Morgan , Fernandez Marty A. , Berg Elizabeth , Prada Adriana , Silverman Jill , Young‐Pearse Tracy , Morrow Eric
Published: December 2022

Background

Loss‐of‐function mutations in the X‐linked endosomal Na+/H+ Exchanger 6 (NHE6) cause Christianson syndrome (CS) in males. CS involves endosome dysfunction leading to early cerebellar degeneration, as well as later‐onset cortical and subcortical neurodegeneration, potentially including tau deposition as reported in postmortem studies. In addition, there is reported evidence of modulation of amyloid beta (Aβ) levels in experimental models wherein NHE6 expression was targeted. For in vivo studies, rat models may have an advantage over mouse models for the study of neurodegeneration, as rat brain can demonstrate robust deposition of endogenously‐expressed Aβ and tau in certain pathological states. Mouse models generally do not show the accumulation of insoluble, endogenously‐expressed (non‐transgenic) tau or Aβ.

Method

We generated an NHE6‐null rat model of CS using CRISPR‐Cas9 genome‐editing technologies to study neurodegeneration in CS and the possibility of Aβ and tau pathology.

Result

Using this novel rat model, we were able to follow the sequence of pathogenic events in CS. NHE6‐null rats demonstrate an early and rapid loss of Purkinje cells in the cerebellum, as well as a more protracted neurodegenerative course in the cerebrum. In both the cerebellum and cerebrum, lysosome deficiency is an early pathogenic event, preceding autophagic dysfunction. Microglial and astrocyte activation also occur early. In the hippocampus and cortex, lysosome defects precede loss of pyramidal cells. Importantly, we subsequently observe biochemical and in situ evidence of both Aβ and tau aggregation in the aged NHE6‐null hippocampus and cortex (but not in the cerebellum). Tau deposition is widely distributed, including cortical and subcortical distributions. Interestingly, we observe tau deposition in both neurons and glia, as has been reported in CS postmortem studies previously.

Conclusion

This new model is among very few examples of a genetically modified animal that exhibits neurodegeneration with deposition of endogenously‐expressed Aβ and tau. This NHE6‐null rat will serve as a new robust model for CS. Furthermore, these studies provide evidence for linkages between endo‐lysosome dysfunction and neurodegeneration involving protein aggregations, including Aβ and tau. Therefore these studies may provide insight into mechanisms of more common neurodegenerative disorders, including Alzheimer’s Disease and related dementias.
A short computerized cognitive training may affect cortical sources of rsEEG rhythms in Alzheimer’s disease patients
Authors: Lizio Roberta , Percio Claudio Del , Noce Giuseppe , Lopez Susanna , Janson Jessica , Barulli Maria Rosaria , Logroscino Giancarlo , Musaro Cinzia , Scianatico Gaetano , Rossini Paolo Maria , Lacidogna Giardano , Gesualdo Loreto , Ferri Raffaele , Soricelli Andrea , Fraioli Lucia , Stocchi Fabrizio , Vacca Laura , De Pandis Maria Francesca , Babiloni Claudio
Published: December 2022

Background

Previous evidence showed abnormal posterior sources of resting‐state electroencephalographic (rsEEG) delta (<4 Hz) and alpha (about 8‐12 Hz) rhythms in patients with Alzheimer's disease (AD) as cortical neural synchronization markers in quiet wakefulness. We tested whether daily computerized cognitive training (CCT), for a short period, with an application of serious games, may affect these mechanisms,

Method

Clinical and rsEEG data were collected in AD and Parkinson's disease (PD) patients with cognitive deficits and normal elderly (Nold) subjects. The rsEEG data in the patients were recorded before and after the two weeks of computerized cognitive training. Cortical rsEEG sources were estimated by exact low‐resolution brain electromagnetic tomography (eLORETA).

Result

AD and PD patients were both characterized by increased performance scores in the execution of the neuropsychological tasks after the CCT program. In AD patients, no statistical difference (p >0.05) was observed in the rsEEG markers after the CCT program. In PD patients, the widespread delta source activities significantly decreased after cognitive training.

Conclusion

These preliminary results suggest that the CCT program with this application of serious games differently affects the cortical neural synchronization mechanisms of rsEEG of the AD and PD patients. In the AD patients, it may have no effect, possibly because of the severely compromised integrity of the cholinergic system in those patients.
An introduction to therapeutic challenges of vascular cognitive impairment
Authors: Elahi Fanny M
Published: December 2022

Background

Neurodegenerative disorders (NDD) are classified based on subtypes of aggregated proteins, regional brain degeneration and associated clinical syndromes. The designation of vascular cognitive impairment, or rather vascular neurodegenerative disorders (VNDD) can apply to any degenerative brain disease where vascular pathologies are considered as drivers of the dysfunction and degeneration. While pathologies can be quantified at autopsy, the diagnosis of VNDD can be made pre‐mortem based on existing vascular risk factors, biomarker abnormalities and presence of neuropsychiatric symptoms. The differences in classification and approach to diagnosis of NDD versus VNDD, however, and the perceived prevalence of none vascular NDD over VNDD pose barriers to therapeutic developments for VNDD. Often, based on A/T/N biomarkers, the pre‐mortem diagnosis of an individual with biomarker abnormalities and cognitive impairment would be AD, even in presence of significant vascular risk factors and imaging biomarker abnormalities.The first question we need to ask is how can we make the diagnosis of VNDD more accurately and more often? The second would be what are the therapeutically targetable cellular and molecular pathologies in VNDD and how diverse is the vascular pathology underpinning neurodegeneration in VNDD? Finally, if we posit that the most therapeutically targetable phase of VNDD is preclinical, prior to clear cognitive deficits, how do we gauge therapeutic efficacy of interventions?

Method

We will review various approaches and designs for therapeutic target discovery in VNDD.

Result

We will also discuss the therapeutic advantages of VNDD.

Conclusion

A paradigm shift on categorization and related perception of NDD etiologies is needed to propel the field into a productive decade of impactful therapeutic discoveries, both for prevention and treatment.
Melatonin Improved Brain Pathologies and Cognitive Dysfunction in Rats with Trastuzumap‐Induced Chemobrain
Authors: Chunchai Titikorn , Ongnok Benjamin , Pantiya Patcharapong , Arinno Apiwan , Khuanjing Thawatchai , Prathumsap Nanthip , Maneechote Chayadom , Pintana Hiranya , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: December 2022

Background

Trastuzumap (Trz) has been shown to significantly increase the survival rate in human epidermal growth factor receptor (HER2)‐positive breast cancer patients, whereas it also causes neuroinflammation, leading to cognitive impairment, as called “chemobrain”. The exact mechanisms of Trz‐induced chemobrain are not fully understood. Melatonin, a hormone derived from the amino acid tryptophan, has been shown to have the neuroprotection in several pathological conditions. However, the effects of melatonin on brain mitochondrial function, microglial morphology, synaptic plasticity, and cognitive function in Trz‐induced chemobrain have never been investigated.

Method

Eighteen male Wistar rats were randomly divided into two groups including control group (0.9% NSS, intraperitoneal (i.p.) injection, n=8) and Trz‐treated group (4 mg/kg for 7 days, i.p. injection, n=16). All Trz‐treated rats were randomly divided into two subgroups (n=8/ subgroup) to receive either vehicle (0.9% NSS, daily via oral gavage) or melatonin (10 mg/kg/day, via oral gavage). At the end of experiment protocol, cognitive function was measured, and brains were obtained for further molecular investigation.

Result

Trz‐treated rats displayed significantly impaired brain mitochondrial function as indicated by increased ROS production, brain mitochondrial membrane potential change, and brain mitochondrial swelling. These parameters were attenuated in melatonin‐treated Trz‐rats (p<0.05, Figure 1). Consistently, Trz administration decreased microglial complexity, as measured by Sholl analysis, which was ameliorated by melatonin treatment (p<0.05, Figure 1). In addition, the results demonstrated that hippocampal plasticity as indicated by dendritic spine density significantly decreased in Trz‐rats, resulting in cognitive dysfunction as indicated by reducing preferent index of novel object location (NOL) and novel object recognition (NOR) test (p<0.05, Figure 1). Melatonin‐treated Trz‐rats improved hippocampal plasticity by increased dendritic spine density, leading to the improvement of cognition by increased preferent index of NOL and NOR (p<0.05, Figure 1).

Conclusion

These findings suggest that melatonin effectively ameliorated cognitive dysfunction in rats with Trz‐induced chemobrain. The novel findings obtained from the present study provided the therapeutic strategies which can be translated into clinical settings for better preventing chemobrain in the future.
An integrated systems‐level analysis of the molecular changes resulting from systemic inflammation and amyloid‐beta immunisation in Alzheimer’s disease
Authors: MacBean Lachlan Ford , Smith Adam R. , Smith Rebecca G. , Boche Delphine , Lunnon Katie
Published: December 2022

Background

Post‐mortem histological examination of active amyloid‐beta immunisation participant brains revealed changes to Alzheimer’s neuropathology, including high levels of plaque removal and increased microglia phagocytic activity. We hypothesise that there are neuroinflammation‐associated changes to DNA methylation in the post‐mortem brain tissue of the study participants. This study was run in parallel with a study investigating the molecular consequences of systemic infections in AD. As systemic infections are linked to the development and onset of AD; we hypothesise that epigenetic and transcriptomic changes arise in microglia because of systemic inflammation and may drive the progression of AD.

Method

PFC and cerebellum tissue was acquired from 16 patients who had received varying doses of the AN‐1792 vaccine or a placebo. PFC tissue was also collected from AD patients who were diagnosed with a systemic infection at time of death (n = 65), AD patients not diagnosed with an infection (n = 70), cognitively normal patients diagnosed with an infection (n = 48). Tissue from cognitively normal patients with no systemic infection diagnosis (n = 66) was also collected, from which age‐matched controls were used for the immunisation study. DNA was extracted from all cases and Infinium methylation EPIC array employed for quantitative interrogation of methylation sites across the genome. Using linear regression analysis, regions of significant differential methylation were identified and annotated to disease relevant genes.

Result

Epigenomic analyses have documented differential methylation dynamics in genes previously associated with AD both globally and in glial cells. This study also shows differences in DNA methylation in key genes in systemic infection cases, both in AD and cognitively normal patients, and immunised brain tissue.

Conclusion

Discovery of disease‐related methylation dynamics in immunised AD brains indicate a specific regulatory response to amyloid‐beta immunisation. Likewise, differential methylation in immunised and systemic infection cases proposes a role for DNA methylation as a key player in regulating microglial phagocytic activity and suggests key biomarkers as potential therapeutic targets.