bluuebunny/crossref_metadata_2025 huggingface dataset:
Importing implementation methods in clinical dementia research
Authors: Grazia Alice
Published: December 2022

Background

Bringing clinical innovation from dementia research to health‐care requires implementing new courses of action. Implementation science methods can help bridge the gap between biomedical research and clinical practice. We imported implementation methods to perform a feasibility analysis for implementing the clinician’s Uniform Dataset‐cUDS as a standard cognitive assessment in two contexts: European academic memory clinics and Italian academic and non‐academic memory clinics.

Method

33 questions, addressing centers' contextual factors, mechanisms of impact, acceptability, hurdles and facilitators were posed to academic and non‐academic memory clinics. The Process Evaluation framework was used as a guidance to evaluate implementation feasibility. Mixed‐methods analyses were performed with SPSS and MAXQDA. We labelled open answers into categories and performed proportion tests for each hurdle and facilitator in both contexts.

Result

46 EADC (European Alzheimer’s' Disease Consortium) academic and 62 SINDem (Italian Society of Neurology on Dementia)(30 academic, 32 non‐academic) clinicians answered the survey. Acceptability towards implementation of cUDS was 65% among EADC and 95% among SINDem responders (p = .134,ɑ = .05). A statistically significant (p = .01) proportion of SINDem clinicians (47%) reported to envision no barrier to the implementation, as compared to EADC clinicians (11%). 59% of EADC centers reported to receive full reimbursement for cognitive assessment versus only 10% in Italian academic centers(p = .58). Qualitative analysis showed similar barriers as the unavailability of material (e.g., local norms) and finances (e.g., insurance, salary) in both EADC‐SINDem centers. Despite non‐statistical significant differences, compared to EADC, SINDem clinicians showed a trend towards greater need of neuropsychologists/specialized staff (EADC: 6%; SINDem: 14‐25%),in particular among non‐academic centers. On the other hand, EADC clinicians seemed more concerned with logistics (EADC: 15%; SINDem: 3%).

Conclusion

Our analysis revealed a good level of feasibility and acceptability for cUDS in Europe, especially in Italy which has no prior local standard as compared to other European countries (e.g., Germany, Netherlands). Similar barriers were identified among Europe and Italy, however, facilitators seemed to be more specific of the country and setting of implementation. This data also revealed structural hurdles, like heterogeneous reimbursement levels for cognitive assessment. Overall, country‐based feasibility analysis are necessary before proceeding into implementation.
Resolving neuroinflammation in AD
Authors: Plath Niels , Balice‐Gordon Rita
Published: December 2022

Background

Human genetics point towards a key role of microglia and microglia expressed genes like TREM2 in neuroinflammation and AD pathology, yet our understanding of microglia spatial and temporal dynamics, therapeutic directionality and translational biomarkers remains limited.

Method and Results

Muna Therapeutics applies structural biology, computational chemistry and human IPSC derived cell assays to develop small molecule agonists for microglial drug targets including TREM2. Introduction of human mutations allows specific drug – target interactions to be probed and has revealed novel small molecule binding pockets, enabling optimized drug design. To identify novel drug targets involved in neuroinflammation, we have built an all‐in‐human spatial transcriptomics and bioinformatics‐based discovery and validation platform. We have assessed >50 human brain samples for pathology‐induced changes in gene expression in microglia and other cells from samples with AD pathology from patients with and without cognitive impairment. This approach has revealed patterns of differentially expressed genes and pathways in brains linked to pathological hallmarks such as Ab plaques and tau tangles, as well as to resilience to the effects of these pathologies. Candidate targets and mechanisms are tested for their impact on neuroinflammation, including directionality, in humanized model systems that also enable translational biomarker discovery and validation.

Conclusion

At Muna Tx, state‐of‐the‐art target discovery and validation as well as structural biology and computational chemistry platforms enable microglia targeted drug discovery and can accelerate therapeutic advancement to clinical development.
Relevance of the pre‐clinical models in TBI
Authors: Crawford Fiona ,   Roskamp Institute TBI Research Team
Published: December 2022

In the absence of any effective translation from preclinical models to clinical application, what has been achieved by laboratory models of TBI? Analysis and assimilation of results from preclinical TBI studies is confounded by the heterogeneity of the models and the TBI paradigms employed. Variance in animal, injury location, severity, number, frequency, age of animal at injury and age of animal at analyses, not to mention the research focus of the investigators themselves, all contribute to the difficulties in data integration and interpretation. Nonetheless, preclinical TBI research has identified areas of focus and enabled creation of timelines of TBI pathobiology. Ultimately, validation of any potential therapeutic targets will require exploitation of the heterogeneity of preclinical models in order to facilitate clinical translation, given the heterogeneity of the patient population.

In the course of modeling TBI paradigms in (primarily) mouse models, the failure of recapitulation of TBI‐dependent neurodegenerative pathology representing AD, PD, ALS etc. has prompted the use of mouse models of neurodegenerative disease, expressing genetic risk factors or humanized for proteins implicated in human neurodegenerative diseases, in efforts to understand how TBI can exacerbate or even precipitate the neurodegenerative pathobiology. These investigations have generated many interesting observations, not always easily consolidated into any clear pathogenic mechanism, but some overarching themes have emerged. Some of the published TBI approaches, and findings, will be reviewed, and knowledge gaps and future directions will be discussed.
Methodological strengths and weakness of cohorts and administrative data for developing population estimates of dementia
Authors: Dobson Annette J , Almeida Osvaldo P , Anstey Kaarin J. , de Crespigny Fleur , Fitzgerald Patrick , Vu Thao Anna , Waller Michael , Flicker Leon
Published: December 2022

Background

There are three main methods of obtaining population data on the incidence and/or prevalence of dementia: cross‐sectional surveys (which may be repeated over time); cohort studies that follow people initially without dementia and count newly diagnosed cases over time; and administrative health records (including linkage of records from multiple sources). The major challenges for all these methods are: how well the study sample represents the target population, the accuracy of diagnoses, and the costs of maintaining the data collection over time.

Method

In a project to improve Australia’s dementia statistics, we conducted a series of studies to compare population estimates of dementia obtained using different methods. Firstly, we used existing general health studies of community‐based cohorts, supplemented by linkage to administrative records of hospital and emergency department admissions, assessments for aged care support, medication prescriptions, and death certificates to estimate the cumulative incidence of dementia. Secondly, we created cohorts based on administrative records for entire populations. Thirdly, we assessed the validity of the identification of people with dementia in the record linkage cohorts in various ways, including linkage with studies that had obtained clinical diagnosis through the standardised assessment of participants.

Result

We will present empirical results illustrating the strengths and limitations of these different approaches. In summary, community‐based cohort studies lack representativeness of national or regional populations due to recruitment biases and differential loss to follow‐up. Cohort studies are also costly to maintain over the long time needed for participants to develop dementia. In contrast, the use of administrative records is relatively inexpensive, but is subject to policy changes that impact on the continuity of data coverage and quality. Population coverage may also be problematic for administrative data if important sources of care for people with dementia are not included; for example, in Australia linkable primary care data are not available. The validation studies showed that accuracy was highly dependent on data sources, and identification of dementia type was unreliable.

Conclusion

Prevalence and trends data of dementia obtained from multiple sources are needed to provide accurate population estimates, together with detailed contextual knowledge and careful analysis.
Efficacy in linguistic characteristics: I‐CONECT project
Authors: Chen Liu , Asgari Meysam , Dodge Hiroko H
Published: December 2022

Background

Researchers have documented ample evidence suggesting progressive decline in linguistic and syntactic abilities due to cognitive decline. Among measures of syntactic complexity derived from natural language processing (NLP) approaches, we hypothesized that the number of
coordinated phrases
(CPs, an indicator of sentence complexity) would improve from an intervention which intended to enhance cognitive function by providing social interactions through frequent video‐chats.

Method

In the I‐CONECT project, the experimental group engaged in a high dose of semi‐structured conversations (four times per week) via video‐chats, with additional weekly 10 minutes telephone check‐ins. The control group received only the weekly telephone check‐ins. We analyzed language samples derived from the weekly phone check‐ins (WPCs) in this study. WPCs mainly ask about social activities engaged by the participant during the previous week with some semi‐structured open‐ended questions. Out of 186 subjects who were randomized to the trial, 113 subjects had at least one recording of WPCs with sufficient recording quality during the 2nd, 3rd and 4th weeks of the intervention (baseline) and during the 3 weeks (i.e., 22, 23, 24th) before the month 6 (M6) assessments. We extracted the number of CPs from WPCs of 52 experimental (25 MCI, 27 normal) and 61 control (34 MCI, 27 normal) participants. We regressed CP scores at M6 on age, gender, years of education, the experimental (vs. control) group, controlling for baseline CP scores using a linear regression model.

Result

Among the MCI group, the experimental group’s CP scores were 0.60 points higher than the control group (p = 0.046) at M6, which is equivalent to over 10 years of age difference in CP scores (i.e., ‐0.055×10 = ‐0.55), controlling for covariates listed above (see Figure 1). Among those with normal cognition, we did not find any significant differences between the two groups at M6 (p = 0.414).

Conclusion

We found that an indicator of sentence complexity improved among the experimental group compared with the control group among the MCI participants. Our results indicated that language measures are capable of tracking clinically meaningful changes in language samples capitalizing their potential use in clinical trials as automated outcome measures.
Social engagement intervention increases dorsal attention network functional connectivity in socially‐isolated older‐old adults: I‐CONECT
Authors: Pruitt Patrick J , Lahna David , Schwartz Daniel L , Peltier Scott , Silbert Lisa C , Dodge Hiroko H
Published: December 2022

Background

Social engagement represents a promising intervention to improve or maintain cognitive function, however the neurobiological mechanism through which social engagement impacts cognitive aging remains unclear. Large‐scale cognitive brain networks facilitate cognitive function and represent a set of likely candidates for being affected by social engagement interventions.

Using resting‐state functional magnetic resonance imaging (rs‐fMRI) data from the Internet‐Based Conversational Engagement Clinical Trial (I‐CONECT), we investigated the effect of social engagement intervention on functional connectivity within large‐scale cognitive brain networks, specifically the default mode network (DMN), salience network (SAL), frontoparietal network (FPN), and dorsal attention network (DAN).

Method

Due to COVID‐19 pandemic, out of 186 randomized participants in the trial, 15 participants were able to complete rs‐fMRI both at baseline and six‐month follow‐up: six participants from the intervention arm (five women; mean age±SD: 79.0±3.8 years) and nine participants from the control arm (six women; 81.2±5.2 years). Nine participants had mild cognitive impairment; six had normal cognition.

Intervention effect was calculated in separate regression models for within‐network connectivity of each brain network, with intervention group predicting connectivity at six‐month follow‐up, controlling for baseline connectivity, age, sex, site, and in‐scanner motion.

Result

In examining the intervention effect on DAN connectivity, the overall regression model was statistically significant (R2= 0.867, p = 0.004; Table 1): The experimental group had significantly higher DAN connectivity at follow‐up (b = 0.25, 95% CI: 0.03 – 0.47, p = 0.031) compared with the control group, (for group x time graph using residualized connectivity values, see Figure 1). Overall regression models for DMN, SAL, and FPN networks were not statistically significant (p > 0.1).

Conclusion

As social engagement interventions emerge as an effective approach to improving cognition in older adults, this work provides novel insight into the impact of such an intervention on large‐scale cognitive brain network connectivity. Specifically, participants who underwent the intervention showed greater DAN connectivity at follow‐up than control participants. The voluntary directed attention facilitated by the DAN is an integral part of social engagement, and this work suggests that DAN merits additional focus in investigations of social behavior in cognitive aging. These findings must be interpreted with caution, due to small sample size.
Astrocytes in Neurodegenerative Disorders
Authors: Escartin Carole
Published: December 2022

Astrocytes are key partners for neurons in the brain. Under pathological conditions, such as neurodegenerative diseases, astrocytes change and become reactive. Even if this response was described more than a hundred years ago, many questions remain about how the reactive state of astrocytes is controlled, and how it impacts their homeostatic functions and surrounding cells.

We have developed molecular tools to modulate and monitor reactive astrocytes in situ, and shown that these cells have multiple and context‐dependent effects in neurodegenerative diseases.

We further aim to identify new molecular targets to promote neuroprotective functions in reactive astrocytes and identify astrocyte‐based biomarkers for brain diseases.
The Interface Of Delirium And Dementia
Authors: Inouye Sharon K.
Published: December 2022

Background

While delirium and dementia are the most common causes of cognitive impairment in older populations, their interrelationship is complex and poorly understood. Dementia is the leading risk factor for delirium, and delirium is an independent risk factor for subsequent dementia. The current evidence for the inter‐relationship of delirium with Alzheimer’s disease and related dementias (AD/ADRD) will be reviewed in detail.

Methods

Dr. Inouye will present an overview of the evidence of the inter‐relationship between delirium and AD/ADRD, including epidemiologic, clinicopathologic, biomarker and mechanistic evidence. Previous studies have shown that 2/3 of persons with ADRD will have at least one hospitalization each year, and 50% will have 2 or more; these hospitalizations are associated with a high risk of delirium. Emerging evidence provides strong support for shared and potentially synergistic pathophysiologic linkages between delirium and ADRD. Key questions to be addressed include: Does pre‐existing AD pathology increase vulnerability to delirium? Does delirium accelerate the pace of cognitive decline in those with AD and ADRD?

Results and Conclusions

At the conclusion of this presentation, participants should be able to:

–Identify the key features of delirium and effective prevention strategies

–Understand the contribution of delirium to worsened cognitive trajectories and outcomes in persons with and without dementia

–Recognize potential shared pathophysiologic pathways between delirium and dementia

–Appreciate that delirium represents an important preventable contributor to dementia
Clinical outcomes of older persons and persons with dementia admitted for COVID‐19: findings from the Philippine CORONA Study
Authors: Anlacan Veeda Michelle M , Piamonte Bernadeth Lyn C , Sy Marie Charmaine C , Jamora Roland Dominic G ,   The Philippine CORONA Study Group, Espiritu Adrian I
Published: December 2022

Background

The coronavirus disease 2019 (COVID‐19) pandemic substantially threatens the health of all populations worldwide, but even more so of vulnerable groups. In our subanalysis of The Philippine CORONA Study, we aimed to determine the impact of older age and dementia on clinically relevant outcomes in COVID‐19 patients.

Method

We included data that were collected in The Philippine CORONA Study, a multicenter, comparative, retrospective, cohort study of 10,881 adult COVID‐19 patients who were admitted between February 2020 and December 2020. Clinical outcomes analyzed were mortality, respiratory failure, duration of ventilator dependence (DVD), intensive care unit (ICU) admission, length of ICU stay (LICUS), and length of hospital stay (LHS) among older persons (individuals ≥ 60 years old) and persons with dementia admitted for COVID‐19 infection.

Result

The adjusted hazard ratios (aHRs) for mortality among the mild and severe cases were significantly higher by 3.93, 95% CI [2.81, 5.50] and by 1.81, 95% CI [1.43, 2.93], respectively, in older patients compared to younger adults. The aHRs for respiratory failure in the elderly were significantly increased by 2.65, 95% CI [1.92, 3.68] and by 1.27, 95% CI [1.01, 1.59] among the mild and severe cases, respectively. The aHR for ICU admission in the older group was significantly higher by 1.95, 95% CI [1.47, 2.59] among the mild cases. Older COVID‐19 patients had significantly shorter median DVD and LHS than younger patients. The aHRs for mortality and ICU admission in persons with dementia were significantly higher by 7.25, 95% CI [2.67, 19.68] and by 4.37, 95% CI [1.08, 17.63], respectively, compared to those without dementia. The group with dementia had a significantly longer median LHS than the group without dementia.

Conclusion

Older age and dementia significantly increased the risk of mortality, respiratory failure, and ICU admission among COVID‐19 patients.
Attenuation of translational repression rescues memory impairment in Alzheimer`s disease mice
Authors: Ribeiro Felipe Campos , Ferreira Danielle Cozachenco , De Felice Fernanda G. , Lourenco Mychael V. , Aguilar‐Valles Argel , Sonenberg Nahum , Ferreira Sergio T.
Published: December 2022

Background

Alzheimer’s disease (AD) is characterized by impaired synaptic plasticity and progressive memory deficits. Converging evidence indicates that hippocampal mRNA translation, required for memory consolidation, is defective in AD. Eukaryotic initiation factor 4E (eIF4E)‐binding protein 2 (4E‐BP2) and Fragile X mental retardation protein (FMRP) act as translational brakes at different stages of protein synthesis. While 4E‐BP2 represses protein synthesis at the initiation step through inhibition of ribosome‐mRNA complex formation, FMRP blocks translation at the mRNA elongation step through ribosome stalling

Method

Aβ oligomers were injected in 3‐month old mice lacking one allele of 4E‐BP2 and one or two alleles of Fmr1. Protein synthesis was assessed by non‐radioactive incorporation of puromycin (SuNSET) in hippocampal slices. Memory performance was assessed by contextual fear conditioning (CFC). Moreover, mice lacking one allele of 4E‐BP2 were crossed with APP/PS1 mice and memory was assessed by CFC at 12 month old.

Result

Genetic reduction of the translational repressors FMRP or 4E‐BP2, prevented the inhibition of hippocampal protein synthesis and memory impairment induced by Alzheimer’s‐linked amyloid‐β oligomers (AβOs) in mice. Moreover, 4E‐BP2 deletion rescued memory deficits in the APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD

Conclusion

Our findings demonstrate that strategies targeting translational repression correct hippocampal protein synthesis and memory deficits in AD models.
Markers of vitamin B12 status in relation to CSF biomarkers and cognitive performance
Authors: Hooshmand Babak , Koch Franziska , Fissler Patrick , Otto Markus , Tumani Hayrettin , Kivipelto Miia , von Arnim Christine
Published: December 2022

Background

The association between markers of vitamin B12 status and cerebrospinal fluid (CSF) biomarkers of Alzheimer’s type dementia which precede cognitive impairment has been investigated by only a few small studies and the results have been inconsistent.

Method

Data included 462 patients aged 40‐94 years referred to the Memory Clinic at the Ulm University Hospital, Ulm, Germany between December 2009 and August 2015. Vitamin B12 and HoloTC were measured via chemiluminescence microparticle immunoassay, tHcy via chemiluminescence immunoassay and MMA via liquid chromatography mass specterometry. High performance liquid chromatography with fluorescence detection was used for measuring vitamin B1 and vitamin B6 whereas electrochemiluminescence immunoassay was used tomeasure folate. CSF Aβ42 and total tau were measured using conventional methods. CERAD battery was used to examine the cognitive status, and different domains were derived. Regression models were used to investigate the associations.

Result

After adjusting for age, sex, creatinine levels and APOEε4 status, higher values of vitamin B12 and lower values of MMA were associated with lower concentrations of CSF total‐tau: the odds ratios (ORs) (95% confidence intervals (CI)) in a binary logistic regression analysis investigating the associations with total tau cut‐off of 400 pg/ml were 0.39 (0.15 ‐ 0.99) and 5.60 (1.93 ‐ 16.26) for the highest quartile of B12 and MMA compared to the lowest, respectively. In addition, vitamin B1 was significantly associated with t‐tau status. Furthermore, HoloTC, MMA, tHcy, vitamin B1, and vitamin B6 were associated with several cognitive domains such as episodic memory and executive functioning. No relationships were found with Aβ42.

Conclusion

Vitamin B12 and vitamin B1 may be independent predictors of CSF biomarkers of Alzheimer’s disease and cognitive status. Randomized controlled trials are needed to determine the importance of supplementing with these vitamins on slowing structural brain changes and cognitive decline in older adults.
FOXO3 longevity genotype protects elderly men with late‐life hypertension from Alzheimer’s disease – Kuakini Honolulu Heart Program
Authors: Chen Randi , Morris Brian J , Donlon Timothy A , Ross G Webster , Willcox Bradley J , Allsopp Richard C , Nakagawa Kazuma , Masaki Kamal H
Published: December 2022

Background

While studies have found that mid‐life hypertension increases risk of Alzheimer’s disease (AD), the association of late‐life hypertension with AD is still unclear, FOXO3 genotype influences mortality risk from cardio‐metabolic diseases (CHD, diabetes, and hypertension). We hypothesize that FOXO3 genotype affects the risk that late‐life hypertension poses to development of AD.

Method

The study involved 2,688 Japanese‐American men (mean age: 77.0 ± 4.1, range 71‐92) from the Kuakini Honolulu Heart Program with FOXO3 rs2802292 genotype, and information on incident AD from 1991 to 2012. Late‐life hypertension was defined as SBP/DBP ≥ 160/95 or taking anti‐hypertensive medication. Here, FOXO3 longevity haplotype (FOXO3‐LH) comprised minor allele frequencies of rs2802292 (G), rs2253310 (C), rs2802288 (A), rs2764264 (C), rs9398171 (C), rs12212067 (G), and rs3800230 (G). The association of FOXO3 genotype with late‐life hypertension and incident AD was assessed using a Cox proportional hazard model.

Result

During 21 years of follow‐up, 513 people were diagnosed with incident AD. Age‐adjusted incidence rates of AD among late‐life hypertensive subjects showed that those with the rs2802292 longevity genotype TG/GG had a lower incidence than those with genotype TT (21.58 vs 24.49 per 1,000 person‐years; p = 0.038). A multivariable Cox model, adjusting for age, education, APOE‐ε4 and other CVD risk factors, showed late‐life hypertension protects men from AD only for those with a longevity genotype such as rs2802292 TG/GG (HR = 0.68, 95% CI 0.52–0.89; p = 0.0052), and with the FOXO3‐LH (HR = 0.59, 95% CI 0.39–0.91; p = 0.016), but this was not seen for the rs2802292 genotype TT (HR = 1.15, 95% CI 0.89–1.49; p = 0.28), nor in the absence of the FOXO3‐LH (HR = 1.14, 95% CI 0.88–1.49; p = 0.31).

Conclusion

This study provides the first evidence that FOXO3 genotype influences the risk that late‐life hypertension has on developing Alzheimer’s disease. Only with the FOXO3 longevity genotype was there protection against a late‐life hypertension‐mediated increase in incident AD risk. The findings have implications for the effect of the FOXO3 longevity genotype on late‐life hypertension‐associated risk of AD. Without considering the effect of FOXO3 longevity genotype, one should be cautious about generalizations concerning the protective effect of late‐life hypertension on AD in the population.
Angiotensin‐(1‐7)/Mas receptor agonist: a disease modifying therapeutic for VCID protects cognitive function and inhibits serum neurofilament light protein
Authors: Hoyer‐Kimura Christina , Konhilas John , Sweitzer Nancy , Ryan Lee , Hay Meredith
Published: December 2022

Background

Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer’s disease related dementias (ADRD) are associated with increases in systemic and brain inflammatory cytokines, increased reactive oxygen species (ROS) and decreased brain blood flow. We have completed preclinical development of novel synthetic glycopeptide derivatives of Angiotensin‐(1‐7) (Ang‐1‐7) MasR agonists that have outstanding brain penetration, improved half‐life, reverse cognitive impairment and decreases plasma neurofilament light protein (NfL) in our preclinical model of VCID. Ang‐(1‐7)/MasR mechanisms of action include inhibition of 1) microglia activation, 2) brain cytokines activation and, 3) vascular endothelial ROS production. The purpose of this pilot study was to 1) determine if plasma NfL is increased in coronary artery bypass graft (CABG) surgery patients at‐risk for VCID and 2) determine if treatment with an Ang‐(1‐7)/MasR agonist protects cognitive function post‐surgy and modifies NfL.

Method

Subjects were randomly assigned to receive either 200 micrograms/kg/day s.c. (n = 3) or saline‐placebo (n = 2). Injections were begun 2 hours prior to surgery and then daily for 21 days. Cognitive function was measured prior to surgery and at 21‐ and 90‐days post‐surgery. Serum NfL was measured via Quanterix Simoa assay. Statistical analysis was performed using GraphPad and significance tested using Welch’s ANOVA, Dunnett’s post. Memory function was measured using a composite score comprised of memory, executive functioning, language, and processing speed.

Result

Plasma levels of NfL prior to surgery were significantly increased by 176% in CABG patients (n = 5) as compared to age‐matched healthy controls (n = 8, p = .003). Treatment with Ang‐(1‐7) for 21‐days via subcutaneous injections protected memory function as measured by both the Face‐Name and Cured Name Retrieval associative memory tests at both 21‐ and 90‐days post ‐surgery and significantly attenuated CABG induced increases in NfL as compared to placebo‐saline treatment (p = .004).

Conclusion

These preliminary data suggest that NfL may serve as a biomarker of VCID in CABG surgery patients and for MasR target engagement for VCID‐modifying treatments with Ang‐(1‐7) analogs. We have begun studies to develop NfL as a biomarker for Ang‐(1‐7)/MasR target activation and for patient stratification for treatment of VCID (Supported by NIH U01HL131014, U01AG066623).
Longitudinal tau accumulation interacts with cortical thinning to predict steeper memory decline in cognitively normal older adults
Authors: Fonseca Corrina S. , Chen Xi , Baker Suzanne L. , Jagust William J. , Harrison Theresa M.
Published: December 2022

Background

Cross‐sectional measures of tau pathology, a hallmark of Alzheimer’s disease (AD), have been associated with brain structure and memory performance in cognitively normal older adults (OA). Fewer studies have explored the downstream effects of longitudinal tau accumulation in OA. Here, we investigated relationships between tau accumulation, atrophy, and memory performance change over time.

Method

Seventy cognitively normal OA (age = 77 ± 5 years; Table1) underwent longitudinal flortaucipir (FTP) PET, structural MRI scanning, and neuropsychological assessment. Annual change slopes for entorhinal cortex (EC) and a temporal meta‐ROI partial‐volume corrected FTP, cortical thickness, and an episodic memory (EM) composite were estimated using linear mixed effects models. Linear methods (Pearson correlation, multiple regression, mixed effects models) were used to relate regional tau slopes to atrophy and EM change. We used elastic net regression to select the best predictors of EM slope, including all FTP and structural ROIs, age, education, beta‐amyloid burden, and sex. Voxel‐wise FTP slope images were also generated to explore associations with atrophy and EM slope across the cortex.

Result

Higher FTP slope in EC and meta‐ROI significantly predicted EM decline (β= ‐.26 p=.03 & β= ‐.38 p=.001, respectively; Fig.1). FTP slope did not significantly predict longitudinal atrophy in EC or meta‐ROI (ps>.10). A multiple regression with predictors selected via an elastic net model (Table2) showed a significant interaction between meta‐ROI FTP slope and EC cortical thickness slope such that tau accumulation and EM decline were more strongly related in OA with a higher rate of entorhinal cortical thinning (β=.23 p=.02; Fig.2). Voxel‐wise models with tau slope and memory showed interesting findings in the temporal lobe but clusters did not reach statistical significance. A one‐sample t‐test showed significant tau accumulation in frontal, parietal, and temporal lobe regions (Fig.3).

Conclusion

EC and meta‐ROI tau accumulation predicts memory decline in cognitively normal OA. EC atrophy moderated the effect of meta‐ROI tau accumulation on memory decline, suggesting a synergic effect of tau pathology and structural atrophy on memory decline in early AD. These novel findings provide insights into mechanisms of memory decline in typical aging and early AD.
Is blood‐based kallikrein‐8 increased in participants with subjective cognitive decline compared to cognitively healthy controls? Results of the Heinz Nixdorf Recall Study
Authors: Jokisch Martha , Krizanovic Nela , Jöckel Karl‐Heinz , Herring Arne , Keyvani Kathy , Weimar Christian , Schramm Sara ,   the Heinz Nixdorf Recall Study Investigative Group
Published: December 2022

Background

While there is rising evidence of blood kallikrein‐8 (KLK8) as a new blood‐based biomarker for mild cognitive impairment due to Alzheimer’s disease (AD) and for AD, little is known about the role of blood KLK8 in earlier prodromal stages of disease. Therefore, the aim of the present study was to examine whether blood KLK8 is elevated in participants with subjective cognitive decline (SCD) compared to cognitively unimpaired controls.

Method

We included 80 participants with incident SCD and 80 controls (matched by sex and age (+/‐ 3 years)) from the population‐based, longitudinal Heinz Nixdorf Recall Study (t0: 2000‐2003, n=4814, ø 57.8 years, 48.3% men; t1: 2005‐2008, n=4157, ø 62.9 years; t2: 2010‐2015, n=3087, ø 68.1 years). A cognitive assessment was conducted at t1 and t2. The cognitive performance of cases and controls was in the normal age and education range at both visits. Cases with incident SCD at t2 did not report SCD at t1. Controls never reported SCD. KLK8 levels at t2 were measured in defrosted serum samples. Using multiple logistic regression the association between KLK8 in cases vs. controls was investigated by estimating odds ratios (OR) and 95%‐confidence intervals (95%CI), adjusted for inter‐experimenter assay variability, freezing duration and depressive symptoms. Using receiver operating characteristic (ROC) analysis the diagnostic accuracy of KLK8 was determined by estimating the area under the curve (AUC) and 95%CI (adjusted for inter‐experimenter assay variability, freezing duration, age, sex, depression).

Result

N=141 participants (50% cases, 36.9% women, 69.5±7.4 years) had valid KLK8 measurements. Mean KLK8 was higher in cases than in controls (1050.1±918.9 pg/ml vs. 834.7±711.6 pg/ml). Fully adjusted, a KLK8 increase of 500pg/ml was associated with a 1.18 (0.92‐1.52) higher chance of having SCD compared to being cognitively unimpaired at t2. With an AUC of 0.71 (0.62‐0.80)) blood KLK8 was a rather weak discriminator for SCD and cognitively unimpaired controls.

Conclusion

This is the first study to show increased KLK8 levels in participants with SCD compared to cognitively healthy controls. However, the diagnostic utility of KLK8 in participants with only SCD seems limited. These results have to be replicated in larger samples.
REMOTE COGNITIVE STIMULATION THERAPY: CONTINUITY IN THE CONTEXT OF COVID‐19 PANDEMIC IN BUENOS AIRES, ARGENTINA.
Authors: Fernandez Maria Cecilia , Murphy Georgina , Melnitzky Agustina , Golimstok Angel , Berrios Waleska , Campora Nuria , Basalo Maria Jose Garcia , Basalo Maria Mercedes Garcia , Quintana Marcos Ojea ,   Memory and Behavior Disorders Research Group of Hospital Italiano of Buenos Aires
Published: December 2022

Background

Due to the COVID‐19 pandemic, clinical practice of neuropsychology has been substantially modified keeping the remote attention since then. In this work our experience in remote cognitive stimulation (RCS) for the past fifteen months and the user satisfaction during the second year of the pandemic is described.

Materials and methods

Surveys were conducted using Google Forms sent via email to patients, relatives or caregivers of patients who agreed to the RCS practice. The degree of difficulty to handle virtual platforms, and the level of satisfaction with the RCS practice were assessed through subjective report of the respondents.

Results

The survey was completed by 121 individuals (67.8% patients and 32.2% relatives). The mean age of the patients who accessed RCS was 75.3, 66.9% were women, 2.6% had incomplete primary school, 34.2% had completed primary school, 42.6% had completed secondary school, 20.6% had completed university and higher degrees.

Regarding the ease of accessing the platform, 56.2.3% referred that it was easy for them. About the degree of satisfaction with the RCS, 65.3% conveyed being very pleased, and 33.1% pleased. 96.7% of those surveyed held that the practice was in accordance with their expectations and 94.2% stated that they would carry out RCS again in the future. Regarding the advantages identified, 52.1.6% recognized as an advantage avoiding the transfer, and 42.1.9% referred a greater use of time.

Conclusion

During the second year of the pandemic we have observed that the satisfaction level regarding remote practice held the same. Patients stood out as principal benefits of it avoiding traveling and the better use of time preferring to continue with this modality. This data allows us to take a glimpse at the benefits of this modality to continue using it in the future regardless of the epidemiological situation.
Glycolysis‐derived L‐serine in hippocampal astrocytes rescues synaptic plasticity and memory loss in a mouse model of Alzheimer’s disease
Authors: Bonvento Gilles
Published: December 2022

Background

Impairment of glycolysis has often been observed early in the course of Alzheimer’s disease, although it is not known whether this deregulation contributes to the cognitive deficits observed in the disease. Aside from ATP production, a major function of glycolysis is to provide precursors, such as L‐serine, to support macromolecular synthesis. L‐serine is a metabolic hub and plays pivotal role in the brain. It is the precursor of D‐serine, the principal co‐agonist of synaptic N‐methyl D‐aspartate receptors (NMDARs) required for the induction of long‐term synaptic plasticity in the hippocampus. It also contributes to the homeostasis of synapses and of mitochondrial function by providing lipids.

Method

We used young female 3xTG‐AD mice to determine whether a shortage in the synthesis of L‐serine produced by hippocampal astrocytes from a glycolytic intermediate is responsible for the impairment of synaptic plasticity and spatial memory.

Result

We found that 3xTG‐AD mice in the early stage of the disease have reduced extracellular L‐serine levels in the hippocampus where in vivo glucose metabolism is reduced, but not in the frontal cortex that does not present metabolic alterations. Acute application of D‐serine or L‐serine rescues long‐term synaptic plasticity and chronic oral L‐serine supplementation restores memory deficits in AD mice. Such chronic treatment also restores the atrophy of hippocampal astrocytes in these AD‐mice.

Conclusion

These results indicate that a metabolic deficit of L‐serine synthesis by astrocytes contributes to cognitive deficits in AD.
Cell sorting after tracer injection to elucidate allocation of cellular FDG uptake in different cell types and different microglial activation states
Authors: Brendel Matthias
Published: December 2022

Background

2‐deoxy‐2‐[18F]fluoro‐d‐glucose positron‐emission‐tomography (FDG‐PET) is widely used to study cerebral glucose metabolism. Radiosorting revealed that the FDG‐PET signal is directly influenced by microglial glucose uptake in mouse models and we found similar associations in patients with neurodegenerative diseases. Now, we questioned the allocation of cellular FDG uptake in the rodent brain.

Method

Single cell [18F]FDG uptake as assessed by magnetic activated cell sorting (MACS) was multiplied with published total cell numbers in the mouse brain, i.e. 71e+6 neurons or 7% (≈ 7.6e+6) microglia cells to estimate the overall uptake per cell fraction. Estimated cellular microglial [18F]FDG uptake as assessed by MACS was cross‐validated with observed %‐FDG‐PET reductions after microglia depletion. Interstitial and vessel [18F]FDG was estimated by interstitial compartment volume and assumed equilibrium of non‐phosphorylated extra‐ and intracellular [14C]Deoxyglucose. Synaptic [18F]FDG uptake was estimated via an enriched synaptosome fraction relative to [18F]FDG uptake of whole‐brain homogenate. A microglia proliferation index of 1.3 was assumed for the whole brain in the Aβ mouse model.

Result

Microglia cells accounted for 8.6% of the overall brain [18F]FDG uptake in wild‐type mice and for 29.9% of the overall brain [18F]FDG uptake in PS2APP mice, confirmed by similar alterations after microglia depletion in PET. Synapses contributed to 13.2‐17.1% of the overall brain [18F]FDG uptake whereas interstitial (5.9‐7.7%) and vessel (2.6‐3.4%) [18F]FDG uptake was of minor magnitude. Neuronal and astrocyte cell bodies accounted for <10% of the overall brain [18F]FDG uptake, but a proportion of 42‐55% was not recovered and likely allocated in lost cell processes, oligodendrocytes and other cell types.

Conclusion

Microglial FDG uptake alterations are the source of FDG‐PET changes in models of neurodegenerative diseases. Our data should increase the awareness to consider glia cells as key contributors of FDG uptake and the detailed proportions of these cellular contributions in healthy brains and under disease conditions deserve deeper investigation.
Identifying relevant psychosocial factors in the Care of People with Dementia: findings of a focus group study with informal caregivers and health professionals
Authors: Ross Sabrina D , Ziegert Nadja , Rodriguez Francisca S
Published: December 2022

Background

Psychosocial factors offer promising possibilities for preventing dementia and slowing its progression. The extent to which psychosocial factors are taken into account in the treatment and care of people with dementia is not well known. The aim of this study was therefore to examine personal experiences and knowledge of psychosocial factors in dementia care structures. Particularly, their influence on dementia symptoms, on coping with daily life as well as on interpersonal relationships and the role of dementia in society.

Method

To identify which psychosocial factors play a role in the treatment and care of people with dementia, three focus groups were held with informal caregivers (1) and health professionals (2) involved in the daily lives of people with dementia. The focus group discussions were transcribed verbatim and analyzed using qualitative content analysis.

Result

It emerges that psychosocial factors have a beneficial effect on daily life performance and general wellbeing, especially social contact. Further, psychosocial factors aid people with dementia in perceiving their general competency and specific abilities. Needs, interests and preserved abilities of people with dementia should be in focus when deciding on psychosocial applications. Perceived barriers to the implementation of psychosocial factors in daily life are bureaucracy, inadequate staffing, cost, and limited offers of and assistance in using psychosocial services. Educating the population about dementia was identified as an important societal challenge in order to counteract a lack of social participation and stigmatization.

Conclusion

The results of our study contribute to a better understanding of the needs psychosocial factors can address successfully. Yet, we also find a number of obstacles to implementing psychosocial factors in the daily life of people with dementia. Many barriers may be overcome by reducing bureaucracy, expanding infrastructure, and increasing dementia awareness as well as time for care activities.
Lipoprotein Lipase Regulates Lipid and Lipoprotein Processing in Microglia
Authors: Bruce Kimberley D
Published: December 2022

Background

Lipoprotein Lipase (LPL) is the rate‐limiting enzyme in lipoprotein hydrolysis. In the brain, LPL is predominantly expressed in microglia and is a key feature of phagocytic disease‐associated microglia thought to be protective in AD. Indeed, we have previously shown that microglia lacking LPL show impaired phagocytosis, lipid uptake, and cholesterol efflux (Bruce et al., 2018; Loving et al., 2021). Since ApoE4‐containing brain‐derived lipoproteins increase AD risk, we investigated how LPL regulates microglial lipoprotein processing.

Method

HDL‐like lipoproteins were isolated from ApoE2, ApoE3, and ApoE4, expressing astrocytes using HPLC. ApoE‐containing lipoproteins were used as substrates in LPL activity assays and cellular lipoprotein uptake experiments. CRISPR‐Cas9 generated LPL knock‐out (LPL KO) cells were used as genetic controls. To further test the role of LPL in the development of AD we generated a novel microglial‐specific LPL knock‐down mouse (MiLPLKD) on the 5xFAD background (MiLPLKD;5xFAD).

Result

ApoE4 containing lipoproteins were hydrolyzed less efficiently than ApoE2 and ApoE3 containing lipoproteins by purified LPL in enzymatic activity assays. In addition, ApoE4 containing lipoproteins were endocytosed less efficiently than ApoE2 and ApoE3 containing lipoproteins by LPL expressing microglia. In contrast, LPL‐mediated lipoprotein uptake was inhibited when lipoproteins were pre‐incubated with Aβ. Finally, MiLPLKD;5xFAD mice showed exacerbated cognitive deficits compared to MiLPLKD or 5xFAD controls.

Conclusion

While LPL mediates microglial‐lipoprotein uptake, both lipoprotein hydrolysis and endocytosis is inhibited in the presence of ApoE4. This suggests that LPL‐mediated lipoprotein uptake is a critical homeostatic mechanism in the brain that is dysregulated in the presence of ApoE4, contributing to AD progression.
Presenilin 2 Knockout Mice are More Sensitive to Acute Valproic Acid in the 6 Hz Model of Focal Seizures
Authors: Lehmann Leanne M , Barker‐Haliski Melissa
Published: December 2022

Background

Patients with Alzheimer’s disease (AD) experience undetected focal seizures, which could worsen overall disease burden (e.g., accelerate cognitive decline and worsen neuropsychiatric comorbidities). Genetic variants in presenilin 2 (PSEN2) are associated with early‐onset AD and result in a loss of normal PSEN2 function, which forms the catalytic component of the g‐secretase enzyme. These patients also experience seizures (Jayadev et al, Brain 2010). Nonetheless, seizures in PSEN2 variant mouse models of AD are significantly understudied (Lehmann et al, Neurochem Res 2021); most prior preclinical work assessing seizure susceptibility and antiseizure drug (ASD) efficacy has been conducted in amyloid precursor protein‐overexpressing models. There are over 30 approved ASDs that may be effective in controlling seizures in AD. However, ASD efficacy and tolerability is not routinely assessed in aged rodent seizure models, nor in models with AD‐associated genotypes. This project thus aimed to establish the dose‐dependent anticonvulsant efficacy of ASDs in the mouse 6 Hz model of focal seizures evoked in PSEN2 knockout (KO) mice.

Method

Male and female PSEN2 KO and WT C57Bl/6 mice aged 3‐4 months were used to determine the median effective dose (ED50) of prototype ASDs (including valproic acid and carbamazepine). ASDs were acutely administered to assess dose‐related seizure control in the 6 Hz test based on our published methods (Koneval et al, Epilepsia 2020).

Result

The ED50 of valproic acid (VPA) in male PSEN2 KO mice was 62.7 mg/kg [48.6‐90.8]; significantly lower than the VPA ED50 for age‐matched male WT mice (158 mg/kg [108‐242]). In females, the VPA ED50 for PSEN2 KO mice was 93.3 mg/kg [39‐159], while in age‐matched WT female mice it was 163 mg/kg [120‐235]. Notably, the ED50 of carbamazepine (CBZ) in male PSEN2 KO mice (14.5 mg/kg [2.23 ‐ 23.6]) was not substantially different from WT mice.

Conclusion

PSEN2 KO mice may be more sensitive to acute administration of VPA than WT mice in the 6 Hz focal seizures model, but this sensitivity is not universal to all ASDs. This study demonstrates that loss of normal PSEN2 function may selectively increase the potency of clinically‐approved ASDs in this preclinical model of focal seizures.