bluuebunny/crossref_metadata_2025 huggingface dataset:
Czech National Action Plan for Alzheimer’s Disease and Related Illnesses 2020–2030: First implementation steps
Authors: Broulíková Hana M.
Published: December 2020

Background

In 2019, Czechia developed a National Action Plan for Alzheimer’s Disease and Related Illnesses (Plan), which will be implemented during the period 2020–2030. The Plan comprises three parts: a vision, a situational analysis, and proposed recommendations. The proposed recommendations consist of almost fifty activities organized around six strategic aims. Unlike its unsuccessful predecessor for the years 2016–2019, the Plan devotes its very first strategic aim to actions concerning development, monitoring and evaluation of the whole implementation process. These include for instance appointing a national dementia coordinator and an advisory stakeholder committee. The substantive strategic aims of the Plan are: 1) national interdisciplinary guidelines and a stronger network of services, 2) education, 3) dementia awareness and prevention, 4) epidemiology and research, and 5) legal protection.

Method

The goal of this conference contribution is to assess continuity between the development and implementation phase of the Plan by evaluating the completion of activities associated with the procedural strategic aim as well as initiated implementation of all other activities. This assessment is based on tools issued by the World Health Organization including Towards a Dementia Plan: A WHO Guide (World Health Organization, 2018). This guide is intended to assist countries in adapting their health and social care systems in order to accommodate the needs of people with dementia.

Result

As of January 2020, the position of the national dementia coordinator was anchored within the Ministry of Health. The works on an implementation roadmap and a first evaluation conference have been initiated. However, neither the coordinator nor the stakeholder advisory committee have been appointed yet. On the other hand, projects implementing some of the recommended activities such as interdisciplinary guidelines are already in the preparation phase.

Conclusion

The Czech National Action Plan for Alzheimer’s Disease and Related Illnesses has transited to its implementation phase.
Is dysregulation of cerebral perfusion an early marker and cause of MCI and AD?
Authors: Marmarelis Vasilis , Shin Dae , Zhang Rong
Published: December 2020

Background

Our previous work has shown that the dynamic vasomotor CO2 reactivity of cerebral vasculature is significantly reduced (p<0.01) in amnestic MCI patients relative to age‐matched controls [Marmarelis et al., J. Alzh. Dis. 56:89–105, 2017]. This quantitative result was obtained through dynamic modeling of the effects of spontaneous changes of arterial blood pressure (ABP) and end‐tidal CO2 (etCO2) upon cerebral blood flow or cortical tissue oxygenation (CTO) measured via Near‐Infrared Spectroscopy at the lateral prefrontal cortex. This study incorporated the dynamic effects of additional contemporaneous changes of heart‐rate (HR), respiratory‐rate (RR) and tidal‐volume (TV) to examine whether and how the intertwined dynamics of these complex mechanisms of physiological regulation influence differentially the cerebral/cortical perfusion in MCI patients versus age‐matched controls.

Method

We employed our novel multi‐variate predictive modeling methodology to quantify the input‐output dynamic relationship between contemporaneous changes of CTO (output) and five input variables: ABP, etCO2, HR, RR and TV, under spontaneous resting conditions. The obtained subject‐specific input‐output predictive models were used to compute indices that quantify relevant physiological mechanisms and compare differences between MCI patients (MP) and control subject (CS).

Result

The obtained model‐based indices were significantly different for MP vs. CS with regard to the dynamic relationships between CTO and etCO2 or TV changes. This is illustrated in Figure 1, where the average model‐kernels (representing the CTO response to a unit‐impulse change of etCO2 or TV) are shown for 40 MP (red line) and 15 CS (blue line), along with SD bounds (dashed lines). Improved delineation between MP and CS resulted (p<0.001) when the obtained model‐based indices of Dynamic Vasomotor CO2 Reactivity (DVCR) and Dynamic Cortical Oxygenation Reactivity (DCOR), respectively, were combined in a composite index defined by the Fisher Discriminant of the respective scatter‐plot (see Figure 2).

Conclusion

Dysregulation of cerebral/cortical perfusion can be detected early and quantified through dynamic predictive modeling of spontaneous hemodynamic/respiratory time‐series data, allowing delineation between MCI patients and controls (p< 0.001) for improved MCI diagnosis. This is viewed as an indication that such dysregulation of cerebral perfusion may be an early trigger/link in the pathogenic cascade towards neurodegenerative disease.
Carotid stiffness is associated with brain amyloid‐β burden in amnestic mild cognitive impairment
Authors: Zhang Rong
Published: December 2020

Background

Vascular dysfunction has been implicated in the onset and progression of Alzheimer’s disease (AD), yet the relationship of arterial stiffening with brain amyloid‐β burden in at risk patients is unclear.

Objective

We aimed to determine the relationship of aortic and carotid arterial stiffening with Aβ burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD.

Methods

Thirty‐two older adults with aMCI underwent 18Florbetapir PET amyloid imaging to ascertain Aβ burden via standardized uptake value ratio (SUVR). Carotid‐femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, and carotid β stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography.

Results

Region‐of‐interest based analysis showed that precuneus and mean cortex Aβ SUVR were correlated positively with carotid β stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP) and APOE4 status. Whole‐brain voxel‐wise analysis showed that Aβ SUVR was positively correlated with carotid β stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aβ SUVR.

Conclusions

Carotid rather than aortic stiffening is independently associated with brain Aβ burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI. Trial Registration: ClinicalTrials.gov identifier: NCT01146717.
ExploreQC: A toolbox for MRI quality control in the EPAD multicentre study
Authors: Lorenzini Luigi , Ingala Silvia , Wottschel Viktor , Wink Alle Meije , Kuijer Joost , Sudre Carole H , Haller Sven , Molinuevo Jose Luis , Gispert Juan Domingo , Cash David M , Thomas David L , Vos Sjoerd , Petr Jan , Wolz Robin , Pernet Cyril , Waldman Adam , Barkhof Frederik , Mutsaerts Henri JMM ,   the EPAD Consortium
Published: December 2020

Background

Magnetic Resonance Imaging (MRI) of the brain is prone to artefacts that may worsen image quality and subsequent analyses. Despite the growing number of large‐scale multi‐institutional imaging studies, standardized approaches for defining inclusion and exclusion criteria on the basis of image data quality are still lacking and quality assessment is often based on visual inspection. We introduce ExploreQC, a MATLAB‐based toolbox which implements a semi‐automatic pipeline to assess QC metrics, select the most relevant parameters, and to derive informed inclusion thresholds.

Methods

The efficacy of ExploreQC was demonstrated on scans from 436 participants of the multi‐centre European Prevention of Alzheimer’s Dementia (EPAD) longitudinal cohort study. Five different MRI sequences from five sites of the EPAD study were used: structural (T1w, FLAIR, diffusion MRI), resting state functional (rs‐fMRI) and ASL perfusion MRI. For each sequence, QC features were selected following a literature review of recently published studies on multi‐parameter QC (Alfaro‐Almagro, F. et al. 2018; Bastiani, M. et al. 2019; Esteban, O. et al. 2017; Fallatah, S. M. 2018; Shehzad, Z. 2015). Similar parameters were grouped in image feature domains (IFDs).

Results

Table 1 shows the 38 QC features within 19 IFDs computed in the EPAD cohort covering each MRI scan‐type. ExploreQC generated within‐ and between‐site distribution plots of each QC parameter to identify outliers for subsequent visual inspection in order to establish the relevance of the parameter (Fig 1).

Conclusions

ExploreQC facilitates the computation and visualization of informative QC parameters, within and between sites and modalities. Application of ExploreQC to the EPAD data showed that the investigation of distributions of different quantitative QC features can provide an overview of the general quality of the data, identify outliers and derive informed reference thresholds for exclusion criteria.
Alzheimer's genetic risk factor FERMT2 (kindlin‐2) controls axonal growth and synaptic plasticity in an APP‐dependent manner
Authors: Eysert Fanny , CoulonVreulx AudreyAnais‐Camille , Flaig Amandine , Mendes Tiago , Grenier‐Boley Benjamin , Demiautte Florie , Amouyel Philippe , Dumont Julie , Kilinc Devrim , Lambert Jean‐Charles , Chapuis Julien
Published: December 2020

Background

Although APP metabolism is being intensively investigated, a large fraction of its modulators are yet to be characterized. In this context, we combined two genome‐wide high‐content screenings to assess the functional impact of miRNAs and genes on APP metabolism and the signaling pathways involved.

Method

We combined genome‐wide high‐content screenings to identify miRNAs (n = 2,555) and target genes (n = 18,107) involved in the APP metabolism. To predict the function(s) of miRNAs that target these genes, pathway enrichment analysis was performed using DIANA Tools mirPath (v3.0). CRISPR/Cas9 technology has been used to generate HEK293 cell lines carrying rs7143400 variant located in the FERMT2 3’UTR and its impact on miRNA binding. Involvement of FERMT2 in axonal growth and synaptic connectivity was assessed using primary neurons cultured in microfluidic devices that fluidically isolate axons from their cell bodies. The functional impact of FERMT2 on CA1 basal synaptic transmission and long‐term potentiation (LTP) has been recorded in ex vivo mouse hippocampal slices, after stereotactic lentivirus injection allowing expression of shNT, shFERMT2 or shAPP.

Result

Our systematic approaches led us to characterize 180 genes targeted by 41 miRNAs as modulators of APP metabolism. Among these genes, we focused on FERMT2, a known genetic risk factor of sporadic AD. We found that FERMT2 directly interacts with APP to modulate its metabolism and that FERMT2 under‐expression impacts axonal growth, synaptic connectivity and long‐term potentiation in an APP‐dependent manner.Lastly, the rs7143400‐T allele, which is associated with an increased AD risk and localized within the 3’UTR of FERMT2, induced a down‐regulation of FERMT2 expression through binding of miR‐4504. This miRNA is mainly expressed in neurons and significantly overexpressed in AD brains compared to controls.

Conclusion

Altogether, our data provide strong evidence for a detrimental effect of FERMT2 under‐expression in neurons and insight on how this may influence AD pathogenesis.
HIV‐associated neurocognitive disorders (HAND) in a cART‐treated cohort of adults aged 50 and over in Kilimanjaro, Tanzania: The first longitudinal follow‐up study of HAND in an older population in sub‐Saharan Africa
Authors: Paddick Stella‐Maria , Holmes Sarah , Ranasinghe Sherika , Mukaetova‐Ladinska Elizabeta , Gray William K. , Urasa Sarah , Dekker Marieke , Dotchin Catherine , Kisoli Aloyce , Howlett William , Lewis Thomas , Kalaria Raj N. , Walker Richard
Published: December 2020

Background

HIV‐associated neurocognitive disorders (HAND) are highly prevalent in Sub‐Saharan Africa (SSA), due to increasing life expectancy and availability of combination antiretroviral therapy (cART). These preliminary data represent the first longitudinal study of HAND in older cART‐treated adults in SSA with the aim of reporting prevalence and persistence of cognitive impairment, and neurocognitive profile.

Method

We investigated prevalence and incidence of HAND diagnosis and subtypes (asymptomatic neurocognitive impairment (ANI), minor neurocognitive disorder (MND) and HIV‐associated dementia (HAD), alongside neuropsychological profile and neurological symptom burden over 40 months in 253 HIV positive adults aged ≥50 attending a government clinic (2016‐2019). HAND diagnoses were reviewed annually by a consensus panel using Frascati criteria, based on detailed clinical assessment.

Result

At baseline (2016), 253 individuals underwent full assessment, of these, 185 were re‐evaluated in 2017, 181 in 2018 and 128 in 2019. 139 individuals had complete data 2016 ‐2018. The majority (68%) were female, median age at diagnosis was 51, and time since diagnosis 7.6 years. Almost all were receiving cART and were well‐managed (mn CD4 532.76. HAND prevalence was 47% in 2016 (n=253, 95.5% cART‐treated) and 49% in 2017 (one‐year incidence from those at risk 37%). Provisional follow‐up data indicates HAND prevalence of 62% in 2018 (n=172) and 54% in 2019 (n=128). Milder forms of HAND predominated, with evidence of reversibility. The predominant cognitive domains affected were both cortical and subcortical (executive function, motor speed, working memory, verbal memory (word list learning) and orientation) with visuoconstruction and language comprehension relatively spared. Both depression and neurological impairments were highly prevalent.

Conclusion

This is the first longitudinal study of neurocognitive impairment in older adults living with HIV in SSA. Findings suggest cART and regular follow‐up are insufficient to prevent occurrence or progression of HAND, though the aetiology remains unclear. Both cortical and subcortical cognitive domains are affected suggesting the possibility of non‐HIV‐related neurodegenerative cognitive decline. If replicated in other SSA settings, HAND is likely to be a major cause of cognitive impairment in older people in SSA, despite cART treatment.
Correlation of insomnia on cognitive functions in perimenopausal and postmenopausal women
Authors: Rothenberg Kasia Gustaw , Bojar Iwona , Humieniuk Ewa , Raczkiewicz Dorota
Published: December 2020

Background

Sleep disturbances as well as cognitive dysfunction are s relatively common and disturbing phenomena in menopause. Little is known however how much cognitive and sleep dysfunctions overlap and influence each other in the population of women transitioning through the menopause.

Method

300, employed women aged 44‐66 were divided into 2 groups according to STRAW criteria: perimenopausal and postmenopausal group. Cognitive functions were assessed by CNS Vital Signs in the following domains: Complex Memory, Verbal Memory, Visual Memory, Psychomotor Speed, Reaction Time, Complex Attention, Cognitive Flexibility, Processing Speed, Executive Function, Simple Attention and Motor Speed. Neurocognitive Index (NCI) is automatically calculated based on: memory, psychomotor speed, reaction time, attention, and cognitive flexibility. Athens Insomnia Scale (8‐item scale, 0‐24 score range) was used to assess insomnia. The t‐test for two means in independent samples was used to compare and Pearson’s correlation coefficient r to correlate theseverity of insomnia and level of cognitive functions. The significance level was assumed at 0.05.

Result

The mean severity of insomnia in the total group of women in the study was 6.70±4.66, which indicates the border of normal range on average. Insomnia was present in 54 (18.00%) of women (Tab. 1). The examined postmenopausal women obtained a significant lower reaction time (87 scores, on average) than those perimenopausal (91 scores, on average) (Tab. 1). Severity of insomnia negatively correlated with the following cognitive functions: complex and visual memories and simple attention in the total group, i.e. the greater the severity of insomnia, the worse the complex and visual memories, and simple attention. Also, a negative correlation was foung between severity of insomnia and simple attention in perimenopausal but not postmenopausal women (Table 2).

Conclusion

The more severe insomnia the worse complex memory, visual memory, and simple attention. In premenopausal group, insomnia corresponded in worsening in simple attention. The results obtained indicate the need for further studies in the area of modulation of the effect of insomnia on cognitive functions in peri‐ and postmenopausal women. This may be important for prophylaxis and treatment of cognitive disorders during perimenopausal transition.
Prevalence of cognitive frailty and associations with other frailty domains in a Spanish community‐dwelling sample
Authors: Facal David , Campos‐Magdaleno Maria , Navarro‐Pardo Esparanza , Pereiro Arturo X.
Published: December 2020

Background

The concept of cognitive frailty has been defined as the simultaneous presence of frailty and mild cognitive impairment in absence of dementia, although recent approaches has considered cognitive frailty as a distinct construct and has taken into account different domains of physical frailty (De Roeck et al., 2020). The aim of the present study is to analyze the prevalence of cognitive frailty in groups with different degrees of cognitive impairment.

Method

A total of 285 community‐dwelling middle‐age and older adults, aged >50 years, from Galicia and Valencia (northwest and southeast of Spain respectively) participated. Cognitive function was assessed using MoCA test, and cognitive complaints with the Spanish version of the Everyday Memory Questionnaire. Participants were classified as objective cognitively impaired, cognitively unimpaired, and cognitively unimpaired with subjective cognitive complaints. Physical frailty criteria included: a) unintentional weight loss or lack of appetite in the last three months; b) self‐reported exhaustion, measured with the General Health Questionnaire‐12 question about affective state; c) weakness, measured with a dynamometer to determine handgrip strength; d) slow walking speed, measured through a timed‐up and go task; and e) low physical activity, measured with the reduced Spanish version of the Minnesota Leisure Time Physical Activity Questionnaire (VREM). Participants were classified as robust if they met none of the criteria, pre‐frail if they met 1 or 2 criteria, and frail if they met 3 or more criteria, corrected by gender and age.

Results

The prevalence of frailty was 2.5% in the cognitively unimpaired group, 12.2% in the group with cognitive complaints, and 9.6% in the group with objective cognitive impairment (chi‐square=18.37;p<0.01) (Table 1). The co‐occurrence with physical frailty is more frequent with slow walking speed and, in the group with complaints, with self‐reported exhaustion.

Conclusion

The prevalence of physical frailty was higher in both cognitive complaints and cognitive impairment groups, compared with the cognitively unimpaired group. The subjective cognitive complaints can play a relevant role in characterizing the relation between physical and cognitive impairments.
Alpha‐synuclein, ferroptosis and neurodegeneration: Investigating a complex relationship
Authors: Ganguly Upasana , Banerjee Anindita , Chakrabarti Sasanka
Published: December 2020

Background

The accumulation of brain iron in several neurodegenerative diseases like Alzheimer’s disease (AD) or Parkinson’s disease (PD) is well established both by ante‐mortem imaging studies and post‐mortem biochemical analysis of affected brain tissue. Thus, understanding the cytotoxic actions of iron in neurons or cells of neural origin would be important in elucidating the mechanisms of neurodegeneration in disorders like AD or PD. We have recently shown that cytotoxic action of iron in SH‐SY5Y cells (catecholaminergic human neuroblastoma cell line) is mediated by accumulated α‐synuclein which triggers mitochondrial dysfunction and cell death. The accumulation of α‐synuclein occurs as a result of decreased clearance from the cell as a result of oxidative inactivation of Parkin. In the current study we have further examined the role of oxidative stress in this process.

Method

SH‐SY5Y cells were treated with ferrostatin‐1, liproxstatin‐1 and vitamin E (ferroptosis inhibitors) and then co‐incubated with 100‐400 μM Ferric ammonium citrate and analyzed for cell death (LDH assay and trypan blue assay), ROS generation (DCFDA assay), lipid peroxidation (MDA levels), reduced glutathione levels and α‐synuclein protein levels (western blotting). α‐synuclein silencing was performed by using commercially available siRNAs.

Result

Our results show that iron induced an increased formation of reactive oxygen species (ROS) and malondialdehyde (MDA) along with a decreased level of reduced glutathione content in SH‐SY5Y cells, and these changes were associated with significant cell death. Co‐incubation of SH‐SY5Y cells with vitamin E, ferrostatin‐1 and liproxstatin‐1, prevented all the toxic actions of iron in our experimental system, and in addition these prevented iron‐induced accumulation of α‐synuclein . These results tend to imply that iron cytotoxicity in our system clearly resembles ferroptotic cell death, and it appears that α‐synuclein could be a key mediator in the latter process. Furthermore, knocking‐down α‐synuclein gene expression by specific siRNA resulted in a significant decrease in oxidative stress induced by iron in SH‐SY5Y cells.

Conclusion

α‐synuclein appears to have a dual role in enhancing oxidative stress as well as functioning as a mediator of oxidative damage to the cells. The implications of these results in neurodegeneration of AD and PD are obvious and need further exploration.
The use of Alzheimer CSF biomarkers in daily clinical practice
Authors: Escudero Joaquin V. , Ladron Gema , Satorres Encarnacion , Timoneda Pilar , Melendez Juan C. , Guarner Jerico
Published: December 2020

Background

Currently, there is a discrepancy regarding whether CSF biomarkers (BM) in Alzheimer’s Disease (AD) should be applied generally in daily clinical practice, performed in high‐level clinical centres, or reserved for research only. The main objective is to assess the influence of these BM on the diagnosis of AD in daily clinical practice, analyzing the change or maintenance of the etiological diagnosis after the performance of the test. As a secondary objective, the type of patients requested to take this test will be assessed. Finally, the concordance between the test request and the recommendations from literature (Shaw et al, 2018) will be analyzed.

Method

This is an observational and retrospective study of patients referred to our hospital’s neurology department for suspected cognitive or behavioral impairment. The patients underwent a CSF study between the years 2014‐2019. For the etiological diagnosis, the most widespread diagnostic criteria were applied at that time (DSM‐IV and NIAA). Main variable: change of pre‐test vs post‐test diagnosis. Secondary variables: concordance with the recommendations, sex, age, symptoms or signs, MMSE, GDS.

Result

102 patients were analyzed, 67.6 a ± 7.9 (49‐84), 53 % men, 75 % with memory loss and 33 % with neuro‐psychiatric symptoms. MMSE: 22 ± 5 (6‐30), GDS: 3 ± 1.2 (2‐6). There was a change in the etiological diagnosis in 39,2 % of the patients, especially when psychiatric disorder was the initial suspicion (34,2 %). There was a complete consistency with the recommendations from literature

Conclusion

The profile of the patient requested for testing was young (compared to the usual age of cognitive disorder), with memory complaints or neuro‐psychiatric symptoms, in the early clinical stages of the disease. The agreement with the recommendations is total. Our change in diagnosis is similar to the one found in other series in literature (Tabaraud et al, 2011), and close to clinical trials using amyloid BM. Therefore, it is believed that CSF BMs are clearly useful in their application under real clinical practice conditions.
Population attributable fraction of dementia risk in individuals with reduced kidney function
Authors: Xu Hong , Garcia‐Ptacek Sara , Trevisan Marco , Evans Marie , Lindholm Bengt , Eriksdotter Maria , Carrero Juan Jesus
Published: December 2020

Background

Community‐based studies regarding the association between chronic kidney disease and dementia risk are conflicting. In a large Swedish population‐based cohort, we explored the incidence and population attributable fractions (PAFs) of dementia risk in patients with chronic kidney disease (CKD).

Method

In the Stockholm CREAtinine Measurements (SCREAM) project, we studied the associations of baseline estimated glomerular filtration rate (eGFR) with the incidence of dementia among 329,822 residents of Stockholm, aged ≥65 years and with no prior history of dementia. The primary outcome was dementia incidence based on ICD‐10 codes or use of anti‐dementia drugs. Secondary outcomes were incidence of the dementia subtypes Alzheimer’s and vascular dementia. The association between eGFR and dementia risk was examined with Cox proportional hazards models. The weighted contributions of kidney disease (eGFR<60ml/min/1.73m2) and other plausible comorbidities to the risk of dementia were quantified using the population attributable fraction (PAF).

Result

18,983 cases of dementia (5.8% of participants) were detected throughout 1,185,304 person‐years. Dementia incidence rates (IR) were progressively higher with lower eGFR: from 6.56/1000 person‐years in persons with eGFR 90‐104ml/min to 30.28/1000 person‐years in those with eGFR<30ml/min). The HR of dementia risk was highest for the presence of CKD [eGFR<60ml/min; HR 1.54(1.28‐1.85)], followed by having a history of stroke [1.51(1.44‐1.58)], diabetes [1.23(1.18‐1.28)], atrial fibrillation [1.09(1.05‐1.14)], and myocardial infarction [1.07(1.01‐1.14)]. The presence of diagnosed hypertension and history of cancer [0.96(0.93‐0.99); and 0.87(0.84‐0.90) respectively] were associated with a lower dementia risk. Via PAF analyses we estimated that 11% [(95% CI (7‐14%)] of the dementia cases were attributed to eGFR<60 ml/min, followed by stroke [4% of cases attributed, 95%CI (4‐5%)] and diabetes [3% of cases, 95% CI (2‐3%)]. PAFs were around 1% for comorbidities such as atrial fibrillation and myocardial infarction. Risk magnitudes were stronger for vascular dementia than for Alzheimer. Sensitivity analyses across predefined strata or after excluding early events yielded similar results.

Conclusion

Reduced kidney function is a strong risk factor for development of dementia, particularly vascular dementia. The proportion of dementia cases attributed to CKD is higher than that attributed to other dementia risk factors such as cardiovascular disease and diabetes.
Biochemical characterization of age‐related calcium‐cAMP‐PKA signaling dysregulation and its effect on tau pathology in rhesus monkey cortex
Authors: Leslie Shannon N. , Datta Dibyadeep , Wang Min , van Dyck Christopher H. , Arnsten Amy F. T. , Nairn Angus C.
Published: December 2020

Background

Early onset forms of Alzheimer’s disease (AD) are driven by rare dominantly inherited genes; however, the predominant form of the disease is sporadic and occurs later in life through an unknown etiology. Sporadic AD emerges after age 60‐65 and preferentially afflicts the association cortex. Thus, a better understanding of how age‐related changes in vulnerable brain regions relate to AD pathology is crucial to developing novel treatments for the disease. AD is characterized by two main pathological hallmarks, tau neurofibrillary tangles and amyloid‐beta plaques. Tau pathology correlates with cognitive decline while amyloid pathology does not. Thus, we focused on the role of age‐related signaling changes on tau pathology. Dysregulated calcium signaling has long been hypothesized to play a major role in age‐related vulnerability to AD1. Thus, we investigated the impact of aging on calcium signaling in the vulnerable dorsolateral prefrontal cortex (dlPFC) of rhesus monkeys, focusing on regulation of and by cAMP‐PKA signaling in relationship to tau pathology. Monkeys provide a unique opportunity to study higher order cognitive circuits unique to primates while still being able to probe molecular networks to a degree that is not possible in human post‐mortem samples. Overall, we found a significant age‐related dysregulation of calcium‐cAMP‐PKA signaling that strongly associated with early stage tau pathology in rhesus monkey dlPFC. (1) Khachaturian, Z. S. C Alzheimer’s & Dementia
13, 178‐182.e17 (2017)

Method

Patterns of molecular signaling were assessed via western blot and immuno‐electron microscopy of monkey dlPFC in animals ranging from 8 to 28 years of age. Mechanistic studies of the relationship between intracellular calcium and tau phosphorylation were performed in rat primary cortical cultures.

Result

We observed a consistent pattern of calcium‐cAMP‐PKA dysregulation in the vulnerable dlPFC region of rhesus monkeys. We found a highly significant association between leaky ryanodine receptor calcium channels and early stage tau phosphorylation (pS214 and pS356). The link between these phosphorylation sites and intracellular calcium was validated through in vitro mechanistic studies.

Conclusion

Age‐related dysregulation of calcium‐cAMP in the dlPFC is associated with early stage tau pathology and may explain the vulnerability of these circuits to degeneration.
Amyloid pathology changes hippocampal GFAP‐positive astrocytes phenotype
Authors: Zimmer Eduardo R. , Bellaver Bruna , Ferreira Pamela C.L. , de Souza Débora Guerini , De Bastiani Marco Antônio
Published: December 2020

Background

Astrocytes are physically intercalated with neurons and a single astrocyte simultaneously exchanges information with multiple neurons. In Alzheimer’s disease (AD), they seem to respond to pathology by becoming reactive, i.e. changing morphology and overexpressing specific proteins, such as the glial fibrillary acidic protein (GFAP). Astrocyte reactivity is one of the earliest brain changes in AD and may serve as a potential target for early diagnosis and treatment. Still, few astrocyte biomarkers have been investigated in AD and, though promising, further development is needed. Therefore, a better understanding of AD‐reactive astrocyte phenotypes is needed. Here, we aimed at evaluating hippocampal astrocytes phenotype in the presence of amyloid pathology in a transgenic AD‐like mice model. We hypothesize that hippocampal astrocytes will react to amyloid‐pathology by assuming a different phenotype when compared to their wild‐type (WT) littermates.

Methods

Hippocampal GFAP‐positive astrocytes data from 10 months‐old male and female PS2APP [Tg(Thy1‐APPSwe,Prnp‐PSEN2*N141I)152HLaoz]mice, which express human APP K670N/M671L and human presenilin 2 N141I mutations, and WT littermates (n = 5 per group) were obtained from GEO dataset(GSE129770) and used to evaluate differentially expressed genes (DEGs) and altered pathways/biological processes. In brief, raw fastq data reads were submitted to quality control assessment. Afterwards, we used the Salmon algorithm on high‐quality RNAseq samples. Finally, DEGs were evaluated using the DESeq2 method. Further data exploration included Gene Ontology (GO) functional evaluation. All RNAseq data analysis were performed using R/Bioconductor.

Results

Principal component analyses (PCA) clearly differentiated gene expression from P2APP and WT astrocytes (Figure 1A). We further identified 1140 up‐regulated and 646 down‐regulated genes in P2APP astrocytes compared to WT (Figure 1B‐C). Interestingly, cell‐to‐cell communication pathways were amongst the top 10 altered GO pathways (Figure 1D). Differences were considered statistically significant at P<0.05.

Conclusion

We identified a striking gene expression signature in hippocampal astrocytes of a mice model presenting heavy load of amyloid‐β. Therefore, changes in astrocyte phenotype, which can impact astrocyte morphology, protein expression and function, may hold the key for the development of novel biomarkers and for advancing our understanding of AD pathophysiology.
Holocaust survivorship and late‐life cognitive performance in men with coronary heart disease
Authors: Weinstein Galit , Lutski Miri , Lital Keinan‐Boker , Goldbourt Uri , Tanne David
Published: December 2020

Background

Holocaust victims experienced extreme physical and mental stress that could lead to prolonged deficits in psychological and physiological well‐being. Indeed, some evidence demonstrates a link between Holocaust exposure and higher incidence of post‐traumatic disorder as well as for cardiovascular morbidity and its risk factors, which in turn are associated with increased brain aging. Recent evidence points to increased dementia risk among Holocaust survivors compared to the general population, however data are limited. We aimed to examine whether exposure to Holocaust conditions is associated with cognitive function and decline in old age.

Method

The study sample included 351 individuals (mean age at baseline 56.7±6.5y) with coronary heart disease (CHD) who participated in the secondary prevention Bezafibrate Infarction Prevention trial in 1990‐1997. During 2004‐2008, these participants underwent a computerized cognitive assessment (mean age 71.8±6.5y). A second cognitive assessment was performed during 2011‐2013 (mean age 77.1±6.4y). Exposure to Holocaust conditions was based on self‐report at the second assessment. Linear regression and mixed‐effect models were conducted to evaluate the associations between Holocaust survivorship and subsequent cognitive performance and rate of decline while adjusting for potential confounders.

Result

Of the total sample, 45 (12.8%) survived concentration camp/ghettos, 70 (19.9%) were Holocaust survivors who escaped concentration camps/ghettos, and 236 (67.2%) were not Holocaust survivors. After adjustment for potential confounders, concentration camp/ghetto survivors had poorer global cognitive performance and poorer attention (β=‐3.90; 95% CI:‐7.11;‐0.68 and β=‐4.11; 95% CI:‐7.83;‐0.38, respectively) compared to individuals who were not exposed to Holocaust conditions. In the longitudinal analysis, participants who reported being at concentration camps/ghettoes had increased cognitive decline in global performance and executive function (β=‐0.19; 95% CI: ‐0.37;‐0.008 and β=‐0.29; 95% CI: ‐0.53;‐0.06, respectively) compared to participants who were not Holocaust survivors. Lastly, those who were Holocaust survivors but not in concentration camps/ghettos had greater decline in attention (β=‐0.11; 95% CI: ‐0.21;‐0.01). Results remained unchanged after excluding individuals with prevalent stroke and dementia and after utilizing Inverse Probability Weighting to adjust for potential selection bias.

Conclusion

Exposure to Holocaust conditions in early‐life may be linked with poorer cognitive function and greater cognitive decline decades later in old‐adults with (CHD).
Alpha‐synuclein N‐ and C‐terminal regions have distinct in vivo roles in mitochondrial fragmentation and oxidation: Implications for a pathogenic mitochondrial pathway for Parkinson’s disease (PD)
Authors: Gunawardena Shermali
Published: December 2020

Background

Mitochondrial health depends on a critical balance between fission via dynamin‐related protein 1 (DRP1) and fusion via mitofusin (MFN) in concert to mitochondrial motility, and defects in fission‐fusion and motility are linked to neuronal dysfunction. In Parkinson’s disease (PD) which is characterized by progressive neuronal loss and α‐syn‐rich Lewy bodies, the presence of impaired mitochondrial function, fragmentation, and high oxidative stress are also seen.

Methods

Using genetics, in vivo reporters of mitochondrial health and biochemical analysis, here we test the physiological relevance of α‐syn in mitochondrial homeostasis using a Drosophila model of PD.

Results

Excess human α‐syn cause fragmented mitochondria, which are rescued by excess/depletion of DRP1, but not by excess MFN. Contrary to previous knowledge, α‐syn aggregation did not contribute to mitochondrial fragmentation as rescue of α‐syn accumulations by excess HSP did not eliminate fragmentation. Further, deletion of the C‐terminus (α‐syn1‐120) or the NAC did not affect mitochondrial fragmentation. α‐syn‐mediated mitochondrial fragments were oxidized as assayed by the in vivo oxidation markers mitotimer, mito‐roGFP2‐ORP1 and mito‐roGFP2‐GRX1, which were rescued by deletion of the C‐terminus. While α‐syn‐mediated oxidized mitochondrial fragments showed biased retrograde motility, α‐syn1‐120‐mediated healthy fragments did not. Intriguingly, α‐syn‐mediated fragmentation was rescued by PINK1/PARKIN expression, but not the fragmentation caused by deletion of the C‐terminus.

Conclusion

Our study demonstrates that under physiological conditions, α‐syn N‐ and C‐terminal regions have distinct functions on mitochondrial fission and oxidation, opening up a previously unknown α‐syn‐mediated mitochondrial defective pathogenic pathway for PD.
Epigenetic measurement of biological age associates with tau load in normal brain aging
Authors: Maroni Marissa J , Wolk David A , Das Sandhitsu R , De Flores Robin , Wisse Laura , Xie Long , Yushkevich Paul A , Lee Eddie B , McMillan Corey T
Published: December 2020

Background

Aging is the most established risk factor for sporadic Alzheimer’s Disease (AD). However, relative risk of AD varies greatly across individuals. One potential explanation for this heterogeneity is that chronological age may not reflect differences in biological aging. One measure of biological age is the “epigenetic clock” which utilizes a weighted statistical model from >350 CpG sites that captures the cumulative work of an individual’s epigenetic maintenance system and has been demonstrated to relate to age, mortality, and survival. In this study, we test the hypothesis that the epigenetic clock will be related to two regional brain aging signatures associated with AD, including neurofibrillary tau tangle (NFTs) load and reduced cortical thickness.

Methods

We evaluated 40 cognitively normal, amyloid‐negative (PET‐Aβ <= 1.11) individuals from the Alzheimer’s Disease Neuroimaging Initiative dataset with DNA methylation, 18F‐Flortaucipr PET, and volumetric MRI data. 18F‐Flortaucipr PET and volumetric MRI data were processed using ANTs Cortical Thickness in 100 neocortical regions of interest (ROI) from the BrainColor/MindBoggle parcellation. 18F‐Flortaucipr PET and T1‐weighted MRI data was additionally processed using ASHS to derive 12 hippocampal subfield parcellations. Regression analyses related chronological age and Horvath’s “epigenetic clock” measurement of biological age to 18F‐Flortaucipr SUVR, mean cortical thickness, and hippocampal subfield volumes.

Results

In healthy adults, we observed a positive association with increasing epigenetic age related to increased tau SUVR in the entorhinal cortex and the hippocampus (p = 0.029, R = 0.36; p = 0.028, R = 0.397). There was no association of epigenetic age with any of the neocortical tau SUVR ROIs and chronological age was not associated with tau SUVR in any of the hippocampal subfields or neocortical ROIs. In contrast, both epigenetic age and chronological age both trended toward associations of reduced cortical thickness in the neocortex.

Conclusions

This study suggests that epigenetic changes that occur with age may provide a risk factor for tau accumulation, more so than chronological age, and that is more tightly linked with age‐related tau pathological accumulation than age‐related cortical neurodegeneration.
Deficiency of WFS1 increases vulnerability to pathological tau in vitro and in vivo
Authors: Chen Shuo , Venkaraman Lalitha , Liang Jiawen , Nakano Yoshi , Villegas Nancy E. Hernandez , Brown Cris , Urano Fumihiko , Koks Sulev , Serrano Geidy E. , Beach Thomas G. , Davies Peter , Diamond Marc , Duff Karen E. , Fu Hongjun
Published: December 2020

Background

Pathological tau accumulates in patients with Alzheimer’s disease (AD) and related tauopathies. However, it remains unclear why specific neuronal subtypes and brain regions are vulnerable to pathological tau in early AD. Recently we found excitatory neurons expressing the Wolframin (WFS1) in the entorhinal cortex and the CA1 of hippocampus are particularly vulnerable to pathological tau in tau transgenic mice and human AD. However, the role of WFS1 in mediating this selective neuronal vulnerability is unknown.

Method

The tau aggregates in live cells were imaged as individual tiles and stitched via the Zeiss Observer 7 fluorescent microscope, and then the area with tau aggregates in each stitched image was quantitated by Image J. The tau pathology in mouse brain was visualized by MC1‐positive and conformation‐dependent tau via the immunofluroscent staining. The protein interaction between WFS1 and tau was measured by the Duolink Proximity ligation assay (PLA) and co‐immunoprecipitation (CO‐IP) assay.

Result

Here we reported that overexpression of human WFS1 significantly reduced DS9 tau seeding in SH‐SY5Y cells stably transfected with P301S mutant tau, while overexpression of mutant P724L WFS1 did not. Also, overexpression of human WFS1 significantly reduced exogenous tau aggregation in primary mouse mixed neurons treated with P301S tau‐YFP lentivirus, while overexpression of mutant WFS1 did not. Furthermore, the heterozygotes of PS19 tau;NestinCre/+; Wfs1f/+
brain‐specific knock‐out mice and PS19 tau;Wfs1+/‐
knock‐out mice have much more tau pathology in the Dentate gyrus, CA1 and entorhinal cortex compared with PS19 tau and PS19 tau;Wfs1f/+
mice. The homozygotes of PS19 tau;NestinCre/+;Wfs1f/f
brain‐specific knock‐out mice and PS19 tau;Wfs1‐/‐
knock‐out mice have even more tau pathology than those heterozygotes. We further identified that WFS1 interacts with both total tau and pathological tau in primary cultured neurons, wild‐type and tau transgenic mice, and human non‐AD and AD cases. The interaction is first enhanced as tau pathology increases, however, it is reduced as tau pathology further increases.

Conclusion

Taken together, we demonstrate that deficiency of Wfs1 increases vulnerability to pathological tau in vitro and in vivo, indicating WFS1 may be a therapeutic target for preventing or delaying the tau pathology in AD.
Plasma YKL40 as a biomarker for brain aging and injury in three community cohorts
Authors: Pase Matthew P , Himali Jayandra J , Bis Joshua C , Beiser Alexa S , Satizabal Claudia L , Aparicio Hugo J , Maillard Pauline , DeCarli Charles , Ghosh Saptaparni , Gudnason Vilmundur , Psaty Bruce M , Tracy Russell P , Launer Lenore J , Fornage Myriam , Seshadri Sudha
Published: December 2020

Background

YKL40 is expressed in reactive astrocytes and microglia and is upregulated in numerous neurological conditions associated with heightened neuroinflammation. We explored the utility of circulating YKL40 as a biomarker of accelerated brain aging and subclinical brain injury.

Method

YKL40 was measured using the Mesoscale Discovery (MSD) multi‐array assay system from stored plasma in three community‐based cohorts: the Atherosclerosis Risk in the Communities Study (ARIC), the Coronary Artery Risk Development in Young Adults (CARDIA), and the Framingham Heart Study (FHS). MRI‐derived outcomes of total brain volume, hippocampal volume, and white matter hyperintensity volume (WMHV) were expressed as a percentage of total intracranial volume. We derived a general cognitive factor from multiple neuropsychological tests capturing multiple domains using cohort‐specific principal component analysis with a forced single factor solution. We examined the association between log‐transformed and standardized YKL40 levels and MRI and cognitive phenotypes separately in each cohort using linear regression. Cohort specific results were then pooled in random‐effects meta‐analysis. Analyses were cross‐sectional and adjusted for age, age squared, sex, education (for cognition), and the time interval between the blood draw for YKL40 and outcome assessment. A second model included additional adjustments for vascular risk factors and presence of the APOE ε4 allele.

Result

Across cohorts, there were 2782 dementia‐free participants (mean age, 64 years; 45% male; Mean(SD) YKL40 levels = 50689(7114)pg/mL; YKL40 Coefficient of Variation = 7.5%). In random‐effects meta‐analysis, higher YKL40 levels were associated with smaller total brain volume (β±SE, ‐0.24±0.05 per percentage change in brain volume, p<0.0001) and poorer cognitive function (β±SE, ‐0.04±0.02 per unit change in cognitive composite, p=0.03). The association between YKL40 levels and total brain volume remained significant following full multivariable adjustments (β±SE, ‐0.23±0.05 p<0.0001) whereas the association between YKL40 and cognition was attenuated (β±SE, ‐0.04±0.02, p=0.06). YKL40 levels were not associated with hippocampal volume or WMHV (P>0.05).

Conclusion

Higher plasma YKL40 levels were associated with MRI and cognitive markers of accelerated brain aging, suggesting involvement of astrocytic or microglial mediated neuroinflammation in subclinical brain atrophy and cognitive impairment.
Defective axonal motility of a unique Huntingtin‐Rab4 vesicle causes synaptic defects and behavioral deficits seen in Huntington’s disease
Authors: Gunawardena Shermali
Published: December 2020

Background

Huntington’s disease (HD) is a progressive neurodegenerative disease characterized by expansion in the polyQ region of Huntingtin (HTT). HTT is ubiquitous but the native function of HTT remains elusive. HTT is required for neuron survival and viability, as loss of HTT causes early embryonic lethality. Although HTT has been implicated to have numerous binding partners involved in a wide array of cellular processes, the significance of these interactions in neurons remain allusive. HTT moves bi‐directionally within axons. However, the specific vesicle types that HTT is present on and the cargoes that HTT‐containing vesicles carry to/from synapses are unknown. Here we test the hypothesis that HTT is involved in the motility of Rab4 whose function remains ambiguous.

Methods

Simultaneous dual‐view imaging and computational analysis coupled with Drosophila genetics is used to isolate moving HTT‐Rab4 vesicles in vivo. Findings are validated in mouse brains and in neurons differentiated from iPSCs from WT and HD individuals.

Results

We found that a sub‐population of moving Rab4‐containing vesicles contained HTT. Reduction of HTT disrupts the bi‐directional motility of Rab4, prompting axonal and synaptic accumulations. Simultaneous dual‐color in vivo imaging revealed that HTT and Rab4 are present on a unique class of vesicles that contain synaptotagmin, synaptobrevin, and/or Rab11, but not APP or Rab3. The HTT‐Rab4 vesicle uses kinesin‐1 and dynein for its bi‐directional movement within axons and is aided by HTT‐interacting protein HIP1 and Rab‐interacting protein Rip11/Rab11‐FIP5, but not HAP1. While pathogenic HTT disrupts Rab4 motility causing larval locomotion defects, synaptic morphological defects and decreased adult lifespan, expression of Rab4 rescues these pathogenic phenotypes. Consistent with these observations, Rab4 motility was perturbed in human neurons derived from HD patient iPSCs, likely due to disrupted associations between the polyQHTT‐Rab4 vesicle and motor proteins.

Conclusions

Our observations propose a model in which HTT links unique Rab4 vesicles to motors for their motility to synapses. Pathogenic HTT perturbs the axonal transport of the HTT‐Rab4 vesicle causing synaptic and behavioral defects. The rescue of these pathogenic defects by excess Rab4 highlight a potential novel therapeutic target for early intervention prior to neuronal loss and behavioral defects observed in HD.