bluuebunny/crossref_metadata_2025 huggingface dataset:
Depressive symptoms modeled across the life‐course are associated with higher risk of dementia and cognitive decline: A pooled cohort analysis
Authors: Brenowitz Willa D , Hazzouri Adina Zeki Al , Vittinghoff Eric , Matthews Karen A , Golden Sherita H , Fitzpatrick Annette L , Yaffe Kristine
Published: December 2020

Background

Depression may be an important risk factor for dementia, but findings are controversial, partially because depression may be an early symptom of dementia. Most studies have only assessed depression symptoms at mid or late‐life, although depression can be a lifelong illness and effects may differ over the life‐course, with important prevention implications. We pooled data from 4 prospective cohorts spanning the life‐course to assess associations between life‐course depressive symptoms and risk of mild cognitive impairment (MCI)/dementia and cognitive decline.

Method

We analyzed repeated Center for Epidemiologic Studies Depression Scale‐10 (CESD‐10) assessments for 15,001 adults spanning early adult to mid‐life (CARDIA; N=5,115), mid to late‐life (MESA; N=4,515), and late‐life (CHS; N=5,888 and Health ABC; N=3,075). Using linear mixed models (LMMs), we imputed expected depressive symptom levels from age 20 until the end of follow‐up, then summarized these exposures in early adulthood (ages 20‐49), mid‐life (50‐69), and late‐life (70‐89) by time‐weighted averages (TWAs). Among CHS and Health ABC participants, we used Cox models and LMMs to estimate the associations of higher depressive TWAs from imputed depressive symptoms with incidence of MCI/dementia as well as cognitive trajectories, adjusting for age, sex, race/ethnicity, education, cohort, and anti‐depressant use. In preliminary analyses, depressive symptoms were categorized as low (CESD‐10= 0‐3; reference group), middle (CESD‐10= 4‐10) and high (CESD‐10 >10).

Result

Increased risk of MCI/dementia was associated with elevated depressive TWAs in each life stage: early adulthood HR=1.59 (95% CI: 1.35,1.87); mid‐life HR=1.94 (95%CI: 1.16, 3.26); and late‐life HR=1.77 (95%CI:1.42, 2.21) (Table 1). Higher TWAs in each life‐stage were also associated with faster rates of cognitive decline (all,p<0.05). When adjusted for depressive TWAs in the other life stages, elevated depressive TWAs in early adulthood (HR=1.73; 95%CI: 1.42,2.11) and late‐life (HR=1.43; 95%CI: 1.08,1.89) remained significantly associated with MCI/dementia and faster cognitive decline.

Conclusion

Depressive symptoms imputed across the life‐course were associated with worse cognition, faster rates of cognitive decline and higher risk of dementia in late‐life. These findings are among the first to suggest that depressive symptoms in early adulthood are associated with higher risk of dementia, independent of the effects of late‐life depression.
The locus coeruleus on stress: Bridging the translational gap
Authors: Bohacek Johannes
Published: December 2020

Background

Loss of locus coeruleus (LC) neurons is one of the earliest and most pronounced features of Alzheimer's disease (AD). Stress is one of the most powerful activators of LC activity, and a risk factor for the development of AD. However, the small size of the LC, and its location deep in the brainstem, make systematic investigations of this nucleus extremely challenging. Here, we develop translational tools that can link animal and human research to study how stress impacts the LC, and how this might contribute to the risk of developing AD.

Methods

First, to study how the LC drives functional changes across brain networks, we developed a new chemo‐connectomic approach that combines DREADD/chemogenetic manipulation of the LC with resting‐state fMRI analyses (rs‐fMRI) in mice. Second, we employ pupillometry – a clinically widespread and readily available tool – together with optogenetic LC stimulation to assess the impact of various, physiologically relevant LC stimulation paradigms on pupil diameter. Third, we leverage novel genetic tools to perform multi‐omic molecular screens in the mouse LC, to analyze sex differences and stress‐induced molecular changes.

Results

Chemo‐connectomics shows that strong LC activation triggers a rapid network reset and potently activates saliency networks, thus revealing striking similarities between LC activation in the mouse and stress‐related rs‐fMRI data in humans. Pupillometry shows that optogenetic LC stimulation faithfully triggers pupil dilation, a response that scales with stimulation intensity and frequency. Molecular screening reveals – for the first time – the impact of acute stress on the transcriptional and translational landscape of the locus coeruleus, while sex differences appear to be subtle.

Conclusion

In combination, these approaches allow us to dissect LC function from molecules to circuits to brain‐wide networks. While pupillometry provides a simple and clinically available window into LC function, chemo‐connectomics holds the potential to identify noradrenaline‐based network signatures that can identify high‐risk populations (or specific subgroups) of AD patients using rs‐fMRI. Finally, the ability to perform high‐throughput molecular screens in mice allows us to explore stress‐induced changes in LC function, and link these changes to neurodegenerative disease processes.
Brain structure and allelic association in Alzheimer’s disease
Authors: Moon Seok Woo , Dinov Ivo D. , Zhao Lu , Matloff William
Published: December 2020

Background

Using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) data archive we examined dementia‐related late‐onset cognitive impairment using neuroimaging and genetics biomarkers.

Method

We used FreeSurfer to parcellate the structural brain magnetic resonance imaging (MRI) data to derive homologous imaging signature vectors composed of 1,118 computed imaging biomarkers. The demographics of the 1,026 ADNI 1, ADNI GO and ADNI 2 arms of the ADNI study included participants ages 405 to 85, 266 normal CN’s (CDR = 0, Male:138, Female:128), 572 mild cognitively impaired MCI’s (CDR = 0.5, Male:227, Female:245), and 188 AD patients (CDR = 0.5/1, Male:102, Female:86). We extracted the AD‐related genetic markers and imaging markers for the network analysis. Using Plink, we modelled the genetics data and the using the Pipeline environment we identified single nucleotide polymorphisms (SNPs) associated with the clinical diagnosis. Network analyses were applied to examine multidimensional imaging‐genetics associations.

Result

The expected significant correlations between the SNPs and the neuroimaging phenotypes were confirmed using neuroimaging genetics networking analyses. These results may explain some of the differences among the AD, MCI and NC groups. We identified many associations between neuroimaging markers and genomic markers. For instance, cortical thickness, e.g., left and right hemispheres mean thickness, was more sensitive than regional volume morphometrics in capturing structural brain changes. We also identified salient neuroimaging (NI) markers that played important roles in neuroimaging networks discrimination between CN and MCI groups. However, regional volumes appeared to be more sensitive than thickness measures in discriminating between the MCI and AD groups.

Conclusion

Structural brain changes are important indicators of dementia progression. Network analysis pairing morphometric biomarkers with genetic indicators allows investigation of clinical and phenotypic associations that facilitate deep systematic understanding of genetic and environmental influences on aging and cognitive decline. Anatomical brain changes reflect the AD complex pathogenesis, their genetic associations, and their longitudinal propagation provide valuable clues to the progression of dementia and differences with normal aging. Further studies are necessary to untangle various deep brain‐networks and interpret their structural association with disease.
The seeding of tau pathology alters the endolysosomal system
Authors: Vazquez‐Sanchez Sonia , Wiersma Vera I. , Kole Jeroen , Jongeneel Rozemarijn , van Beek Roderick , Bebelman Maarten , Scheper Wiep , van Weering Jan
Published: December 2020

Background

Tau pathology and endolysosomal alterations co‐occur in brains of Alzheimer’s Disease and other tauopathy patients, but the relationship between these two pathological features is currently not understood.

Method

Tau pathology can be modeled in vitro by seeding recombinant tau fibrils on human tau expressing cells, recapitulating tau hyperphosphorylation, misfolding and aggregation. The present study addressed how the seeding of tau pathology impacts the endolysosomal systemin various cell models. Cells expressing human GFP‐tau‐P301L were seeded with pre‐aggregated tau and fixed after 10 days for confocal and 3D‐STED analysis.

Result

Tau seeds were observed in early and late endosomal/lysosomal compartments. In iPSC‐derived human neurons, the seeding of tau pathology decreased the number, size and EEA1 labelling intensity of EEA1‐positive early endosomes. The effect on early endosomes was specific as the morphology of LAMP1‐positive late endosomes was not affected. Our data however did indicate a decreased proteolytic activity of these compartments suggesting that tau pathology seeding can causally affect endolysosomal function.

Conclusion

The seeding of tau pathology can causally induce changes in the endolysosomal system, both on the morphological and the functional level. Such disturbances of this important recycling pathway in neurons may play a critical role in neurodegeneration observed in tauopathies.
Heterogeneous polygenic predisposition to Alzheimer’s disease in the Apolipoprotein E region
Authors: Kulminski Alexander M. , Philipp Ian , Loika Yury , He Liang
Published: December 2020

Background

Despite recent advances, the role of genetic variants in the ApoE region in Alzheimer’s disease (AD), including ApoE4 and ApoE2 alleles, is still controversial. For example, although most researchers believe that the strongest adverse genetic association between the ApoE4 allele and AD is due to this allele itself, others argue that this link is mediated by variants from non‐ApoE genes in this region. A role of the potentially beneficial ApoE2 allele in AD is even more controversial.

Method

We used the standardized third mixed moment (coskewness) metric, which generalizes linkage disequilibrium (LD) between pairs of single nucleotide polymorphisms (SNPs), to gain insights into a more homogeneous polygenic architecture of AD in the ApoE region. We examined coskewness using genotypes of 32 SNPs representing BCAM‐NECTIN2‐TOMM40‐ApoE‐ApoC1 region in a mega sample of 2,799 AD‐affected and 16,354 unaffected Caucasians from four independent studies. Associations of triples of SNPs with AD were assessed by contrasting the differences in coskewness between AD‐affected and unaffected subjects. We emphasized coskewness for triples harboring ApoE2 (rs7412) and/or ApoE4 (rs429358) coding SNPs.

Result

For 32 SNPs, there were 4,960 triples. The analysis of the mega sample of four studies combined identified 306 triples of SNPs from all five genes associated with AD at Bonferroni‐adjusted significance level (p < 10−5 = 0.05/4960). Of them, 275 triples (90%) were validated by examining consistency of directions of the associations in two subsets of independent studies comprising this mega sample that is widely regarded as replication. Of these 275 validated triples, 43 triples included rs429358 and 17 triples included rs7412. In addition, three triples included both these SNPs and SNPs from TOMM40 (rs2075650), ApoE (rs405509), and ApoC1 (rs12721046) genes. For a vast majority of validated triples, the associations with AD were not explained by pairwise LD between SNPs.

Conclusion

These results indicate AD‐associated structuring genetic processes in Caucasians. They provide compelling support for heterogeneous polygenic predisposition to AD in the ApoE region in the form of compound genotypes and haplotypes. They suggest coherent, rather than independent, role of the ApoE2 (rs7412) and ApoE4 (rs429358) coding SNPs and other SNPs in the ApoE region in AD.
World Alzheimer Report 2019: Attitudes to dementia, a global survey
Authors: Lynch Chris
Published: December 2020

Background

In 2019 Alzheimer’s Disease International (ADI) undertook the biggest global survey on attitudes to dementia, with 70,000 people across 54 countries participating. Alongside expert essays, case studies and programmes to tackle stigma, the survey results formed the core of the 2019 World Alzheimer Report

Method

ADI commissioned London School of Economics & Political Science to create and design a global survey engaging 4 distinct audiences: people living with dementia, carers, healthcare professionals and the general public. The survey was distributed online, through the ADI network, with an offline/supported option for assisted completion.

Result

Headlines. 95% of respondents think they will develop dementia in their lifetimes. 78% are concerned. 2 in 3 people think dementia is a normal part of ageing. 62% of healthcare practitioners that resounded believe dementia is a normal part of ageing. 1 in 4 believes there is nothing you can do about it. 82% would take a genetic test. 54% believe lifestyle factors play a part in developing dementia.

Conclusion

Three years after the introduction of the WHO Global action plan on dementia, with a clear objective of raising awareness, it is evident that stigma is still one of the major barriers to people seeking out information, advice, support and even a diagnosis. Increasing awareness and tackling stigma is vital, not only to help improve the lives of those living with a diagnosis but to ensure that risk reduction messages have impact. There is evidently also still a need to improve understanding of dementia as a medical condition, and not just a normal part of ageing, for both the general public but also healthcare practitioners.
Proteomics studies to investigate alterations in the tau interactome under conditions of elevated cellular O‐GlcNAcylation
Authors: Choi Jinkuk , Walther Dirk M. , Bajrami Bekim , Halftermeyer Anais , Rajamohamed Sait Hameetha Banu , Okugawa Naomi , Engle Sandra J. , Wei Ru , Hering Heike
Published: December 2020

Background

Neurofibrillary tangles consist of tau protein aggregates and represent a hallmark pathology of Alzheimer’s disease. Tau aggregation, specifically the formation of early aggregates, is believed to be neurotoxic. O‐linked glycosylation of proteins with β‐linked N‐acetylglucosamine (O‐GlcNAcylation) is exclusively mediated by two enzymes in cells, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA). Importantly, increasing O‐GlcNAcylation attenuates tau aggregation in cell‐free systems and cells and reduces tau pathology in various animal models, but the underlying molecular mechanism is still unclear. We aimed to determine how protein‐protein interactions of tau are affected by altered O‐GlcNAcylation levels in cells.

Method

(1) Immunoprecipitation of tau complexes and nano LC‐MS/MS analysis (IP‐MS) were performed to detect changes in tau binding proteins in HEK293T cells, upon elevated O‐GlcNAcylation by OGT overexpression and OGA inhibition. (2) Proximity labeling by TurboID, an engineered biotin ligase, fused to either wild‐type or O‐GlcNAcylation‐resistant mutant tau and nano LC‐MS/MS analysis were performed to assess changes in the proximity of tau to other proteins in iPSC‐derived human cortical neurons (iN), after increasing O‐GlcNAcylation by OGA inhibition.

Result

(1) We detected proteins that constitutively or differentially interact with tau from IP‐MS experiments in HEK293T cells. Microtubule and cytoskeletal proteins were consistently bound to tau regardless of changes in cellular O‐GlcNAcylation. RNA binding proteins and ribosomal proteins increased but cytosolic/exosome proteins and chaperone proteins decreased their interaction with tau upon elevated cellular O‐GlcNAcylation. (2) Proximity labeling of proteins by TurboID‐tau in iN successfully identified microtubule‐associated proteins and proteins that were previously reported to interact with tau in the brain. Interestingly, six proteins significantly changed their proximity to O‐GlcNAcylation‐resistant mutant tau, whereas increased O‐GlcNAcylation by OGA inhibition did not change the proximity labeling profile of wild‐type or mutant tau proteins.

Conclusion

These results demonstrate that increasing cellular O‐GlcNAcylation does not significantly alter the general subcellular localization of tau, but affects its interaction with specific binding partners, some of which were previously implicated to play important a role in neurodegeneration. These data may provide novel mechanistic insights into how O‐GlcNAcylation impacts tau pathology.
Long‐term synaptic depression and memory deficits are reversed by enhancement of GirK‐dependent signaling in a mouse model of early amyloidopathy
Authors: Jimenez‐Diaz Lydia , Sanchez‐Rodriguez Irene , Djebari Souhail , Temprano‐Carazo Sara , Yajeya Javier , Iborra‐Lázaro Guillermo , Vega David , Jimenez Raquel , Navarro‐Lopez Juan D.
Published: December 2020

Background

Hippocampal synaptic plasticity disruption by amyloid‐β (Aβ) peptides is thought to be responsible for learning and memory impairments in Alzheimer's disease (AD) early stage. Failures in neuronal excitability maintenance seems to be an underlying mechanism. G‐protein‐gated inwardly‐rectifying potassium (GirK) channels control neural excitability by hyperpolarization in response to many G‐protein‐coupled receptors activation.

Method

Here, in early in vitro and in vivo amyloidosis mouse models, we study whether GirK channels take part of the hippocampal synaptic plasticity impairments generated by Aβ
1‐42. In vitro electrophysiological recordings from slices showed that Aβ
1‐42 alters synaptic plasticity by switching high frequency stimulation (HFS) induced long‐term potentiation (LTP) to long‐term depression (LTD), which led to in vivo hippocampal‐dependent memory deficits.

Result

Remarkably, selective pharmacological activation of GirK channels with ML297 rescued both HFS‐induced LTP and habituation memory from Aβ
1‐42 action. Moreover, when GirK channels were specifically blocked by Tertiapin‐Q, their activation with ML297 failed to rescue LTP from the HFS‐dependent LTD induced by Aβ
1‐42. On the other hand, the molecular analysis of the recorded slices by western blot showed that expression of GIRK1/2 subunits, which form the prototypical GirK channel in the hippocampus, was not significantly regulated by Aβ
1‐42. However, immunohistochemical examination of our in vivo amyloidosis model showed Aβ
1‐42 to downregulate hippocampal GIRK1 subunit expression.

Conclusion

Together, our results describe an Aβ‐mediated deleterious synaptic mechanism that modifies the induction threshold for hippocampal LTP/LTD and underlies memory alterations observed in amyloidosis models. In this scenario, GirK activation assures memory formation by preventing the transformation of HFS‐induced LTP into LTD.
Morphofunctional changes and expression of LAMP2 in the rat hippocampus in chronic cerebral ischemia
Authors: Smirnov Alexey Vladimirovich , Mednikov Dmitry , Tyurenkov Ivan Nikolaevich , Kurkin Denis , Zamlelov Alexander
Published: December 2020

Background

The hippocampus, part of the limbic system, is involved in the formation of the cognitive sphere and is one of the most vulnerable structures in chronic cerebral ischemia.

Method

Chronic cerebrovascular disorders modeled in rats by limiting blood flow with applying ligatures to the carotid arteries. Behavioral status, cognitive and mnemonic functions, the degree of neuronal damage, and the level of LAMP2 expression in the pyramidal layer of the hippocampus were investigated.

Result

After a 20‐day subtotal cerebral ischemia, we revealed a change in the functional state of the nervous system, expressed in a decrease of the main reflexes, tentative‐research activity, as well as a decrease in memory. Dystrophic changes in pyramidal neurons were of different severity, determined by a significant increase in the number of hyperchromic neurons, and in most of them total nuclear and cytoplasmic hyperchromia was observed, combined with a picture of spongiosis due to pericellular edema. A significant increase in LAMP2 expression compared to the control in both the relative area by 0.8% (p <0.05) and the intensity of the expression was detected in the CA1 zone.

Conclusion

The amplification of LAMP‐2 expression is a marker for the inclusion of autophagy mechanisms aimed at implementing compensatory processes in many disorders of the central nervous system, including chronic cerebral ischemia. The observed increase in the specific number of pyramidal neurons with signs of damage, sharp pericellular and perivascular edema in combination with increased expression of LAMP‐2 in the CA1 zone of the hippocampus indicates the important role of autophagy for the survival of neurons in chronic cerebral ischemia.
In‐vitro neuronal cell proliferation and in‐vivo neuroprotective activity of pinus roxburghii for memory and cognition
Authors: Sharma Aditi , Goyal Rohit
Published: December 2020

Background

Pinus roxburghii Sarg. is traditionally used as a nerve tonic, hemostatic and anticonvulsant. The present study was aimed to investigate the neuroprotective activity of P. roxburghii stem bark for memory and cognition using in‐vitro and in‐vivo methods.

Method

Plant drug was extracted with methanol using Soxhlet extraction. In‐vitro cell viability activity of P. roxburghii was assessed using PC‐12 cell lines. The in‐vivo neuroprotective activity of P. roxburghii was tested on Wistar albino rats (either sex) and ICV‐STZ (3 mg/kg, bilateral) was given to cause memory deficit. HPTLC fingerprinting was performed for the presence of quercetin and gallic acid in the plant extract.

Result

The phytochemical testing of extract revealed the presence of flavonoids, alkaloids, steroids, and tannins. P. roxburghii showed significant cell viability at 10, 50 and 100 µg/ml in an in‐vitro test on PC‐12 cell lines. In the in‐vivo activity, ICV‐STZ caused significant deterioration in memory and cognition, tissue oxidative stress and AchE activity. P. roxburghii 100, 200 and 300 mg/kg, p.o. and donepezil (3 mg/kg, p.o.) significantly (p<0.05) reversed the behavioral changes in rats when tested on morris water maze and elevated plus maze. Increased levels of lipid peroxidation, AchE activity and decreased the level of glutathione were significantly (p<0.05) antagonized by P. roxburghii, similar to donepezil in rat brain. Quercetin and gallic acid were identified quantitatively in the plant extract in HPTLC study.

Conclusion

The methanolic extract of P. roxburghii ameliorated ICV‐STZ induced cognitive deficits and memory impairment possibly due to the presence of quercetin and gallic acid.
The implication of SRC family kinases in Alzheimer’s disease
Authors: Beirute‐Herrera Julianne L. , Diouf David , van den Hove Daniel L.A. , Mastroeni Diego F.
Published: December 2020

Background

Alzheimer’s disease (AD) remains as one of the major challenges for the neuroscientific community today. It affects approximately 50 million cases worldwide, with a total cost estimation of $290 billion in 2019 (Alzheimer’s Association, 2019). The pathophysiological hallmarks of AD are amyloid beta plaques (Aβ) and neurofibrillary tangles (NFTs). Nevertheless, the underlying mechanism have yet to be elucidated (Mehta et al., 2017). Recent efforts have demonstrated that non‐receptor Src‐family tyrosine kinases in AD are potential targets for therapeutic intervention and we show epigenetic mechanisms associated with the expression of non‐receptor Src‐family tyrosine kinase (e.g. methylation), as a mechanism for its dysfunction (Kaufman et al., 2015; Iatrou, Kenis, Rutten, Lunnon & van den Hove, 2017). The current project aims to investigate the proteomic, genomic and epigenomic correlation of c‐ and v‐SRC to PYK2 and Fyn in neuropathologically confirmed AD and nondemented control cases.

Method

Western blots, immunohistochemistry, qPCR and Methylation Specific PCR will be performed in the Medial Temporal Gyrus (MTG) of 10 AD cases in a range of disease states (Braak stage IV, V and VI) and in 10 healthy age matched controls (Braak stage 0‐II). Laser Capture Microdissection will be used prior to qPCR to select neurons and microglia. For the statistical analysis, a 2‐tail student t test and regression analysis of expression profiles will be conducted using IBM SPSS Statistics 25.0 with a significance level of >0.05 and covariates like Braak stage and gender.

Results

Preliminary results already showed a significant upregulation of v‐Src and Fyn in CA1 laser capture neurons in AD cases compared to controls. While immunohistochemistry shows an upregulation of the Src family kinases in the CA1 of the AD cases. We hypothesize that there is an upregulation of c‐Src, v‐Src, Fyn and PYK2 mRNA/protein levels in AD cases, which is correlated to hypomethylation in the promoter regions of the corresponding genes in AD cases. Furthermore, is expected that the same proteins interact in both microglial and neuronal cells following an equivalent pattern.

Conclusion

V‐Src and Fyn are upregulated in Alzheimer’s disease cases and must be considered to further study the pathophysiology of the disease.
The C99 fragment of APP regulates cholesterol trafficking
Authors: Montesinos Jorge , Pera Marta , Larrea Delfina , Guardia‐Laguarta Cristina , Area‐Gomez Estela
Published: December 2020

Background

γ‐secretase activity is enriched at mitochondria‐associated ER membranes (MAMs),a lipid‐raft subdomain of the ER, where APP fragment C99 is delivered for its cleavage. Moreover, γ‐secretase activity deficiency linked to AD mutations causes C99 accumulation at MAM, resulting in the upregulation of MAM activities such as sphingomyelin turnover and cholesterol esterification. We now explore whether the interaction of C99 with cholesterol could explain the link between C99 accumulation at MAM and the lipid abnormalities found in AD.

Method

Using cellular models of C99 accumulation versus a cholesterol‐binding deficient C99, we assessed cholesterol uptake dynamics and sub‐cellular distribution along with MAM‐regulated functionalities such as cholesterol esterification, phospholipid synthesis and sphingomyelinase activity. Also, we used a photo click activable cholesterol analog to study the proteins interacting with cholesterol at MAM in both conditions.

Result

C99 accumulation at MAM caused an increase in cholesterol uptake, cholesterol esterification, phospholipid synthesis and sphingomyelinase activity accompanied by a sub cellular redistribution of cholesterol to endolysosomes and ER, while C99‐defective in cholesterol binding showed no changes in these activities. Moreover, when the cholesterol‐interacting proteome of both conditions was compared, C99 caused a huge change/recruitment at MAM, especially of enzymes involved in lipid metabolism.

Conclusion

We report that the lipid alterations caused by pathogenic C99 accumulation are a consequence of an exacerbated uptake of extracellular cholesterol and mobilization towards MAM. The increase content of cholesterol at MAM driven by C99 might be responsible of the persistent activation of MAM and a subsequent alteration of the lipid metabolism since a cholesterol‐binding deficient C99 fails to increase MAM activities and cholesterol trafficking.
Differential effects of confluent and non‐confluent white matter hyperintensities on functional connectivity in mild cognitive impairment
Authors: Kumar Dilip , Vipin Ashwati , Wong Benjamin , Ng Kok Pin , Kandiah Nagaendran
Published: December 2020

Background

Emerging evidence suggests that confluent WMH results in greater cognitive impairment compared to non‐confluent WMH. However, the mechanism linking confluent WMH and early cognitive impairment is not clearly understood. We studied the effects of confluent and non‐confluent WMH on whole‐brain functional connectivity (FC) across 164 regions of interest (ROI) in subjects with Mild Cognitive Impairment (MCI).

Method

Sixty‐three MCI subjects with T1‐weighted MRI, T2‐weighted MRI, resting‐state functional MRI (rs‐fMRI) and neuropsychological data were studied. Subjects were classified as confluent WMH (C‐WMH) or non‐confluent WMH (NC‐WMH) using the Staal’s criteria on the Fazekas WMH scale. Group‐level ROI‐to‐ROI FC trends and differences at differential WMH subtypes were computed using standard rs‐fMRI analysis.

Result

Subjects with C‐WMH exhibited increased inter‐regional FC in the fronto‐parietal, fronto‐occipital, parieto‐occipital, and temporo‐parietal regions of the salience, dorsal‐attention, default‐mode, and visual networks. Increased intra‐regional FC in the frontal lobe was also observed in C‐WMH. In contrast, only intra‐regional FC changes were seen in the frontal and temporal lobes in NC‐WMH. Performance on the Montreal Cognitive Assessment correlated positively with increased inter‐regional FC only in the C‐WMH group, suggesting that increased connectivity was associated with better global cognition in MCI subjects with C‐WMH.

Conclusion

C‐WMH in subjects with MCI is associated with widespread increased inter‐regional FC changes which correlates with better performance in global cognition. These findings provide novel insights into divergent functional alterations related to the confluence of WMH in MCI.
The association of depression with structural brain markers and cognitive impairment: The Maastricht study
Authors: Geraets Anouk F.J. , Schram Miranda T. , Jansen Jacobus F.A. , Koster Annemarie , Dagnelie Pieter C , Greevenbroek Marleen M.J. , Stehouwer Coen D.A. , Verhey Frans R.J. , Koehler Sebastian
Published: December 2020

Background

The risk of dementia is doubled in depression. However, the underlying etiology remains unclear. Clinical studies suggest that depression is related to brain atrophy and cerebral small vessel disease (cSVD), which are themselves related to cognition. We studied the associations between depression, structural brain markers and cognition in a general population aged between the 40 and 75 years.

Method

We used cross‐sectional data from the Maastricht Study (n=7,066; mean age 59.6±8.7 years, 50.1% women), which, by design, oversampled participants with type 2 diabetes (T2D). Major depressive disorder (MDD, n=236) was assessed by the Mini‐International Neuropsychiatric Interview. From a comprehensive neuropsychological battery, we derived standardized sum scores on tests for memory, information processing speed, and executive functioning and attention. Presence of significant overall cognitive impairment was defined as a score <‐.1.5 SD below norms scores for age, gender and education. Volumes of cerebral spinal fluid (CSF), white matter (WM), grey matter (GM) and white matter hyperintensities (WMH), and presence of lacunar infarcts, cerebral microbleeds and total cSVD burden were assessed by 3 Tesla MRI. Multiple linear and logistic regression analyses tested the associations between MDD, brain markers and cognitive functioning, adjusted for a range of demographic, cardiovascular, and lifestyle risk factors.

Result

In fully adjusted models, MDD was associated with lower scores in memory (B=‐0.11(‐0.22;0.00)), information processing speed (B=‐0.24(‐0.32;‐0.15)), executive functioning and attention (B=‐0.23(‐0.32;‐0.14)), and with presence of significant cognitive impairment (OR=2.37(1.77;3.17)). In those with available MRI data (n=4,734), MDD was associated with a lower GM volume only in older participants (p‐interaction=0.023), and with total WMH (B=0.17(0.01;0.34)), periventricular WMH (B=0.18(0.01;0.35)), and total cSVD burden (OR=1.70(1.09;2.65)) in participants without T2D (OR=1.70(1.09;2.65)).

Conclusion

This study shows that MDD is associated with cognitive impairment, including worse memory, information processing speed, and executive functioning and attention, independent of major demographical, cardiovascular and lifestyle risk factors. In older participants, MDD is related to a lower GM volume, while in the wider general population without T2D, MDD is related to markers of cSVD burden. Longitudinal studies are needed to examine the role of structural brain damage in the development of cognitive impairment and dementia in depression.
Polypharmacy in long‐term care residents: Prevalence and relationships with age and dementia
Authors: Zhang Er Dong , Kelly Ronald , Arvan Tara , Chinda Betty Nhuoma , Low Hilary , Song Xiaowei
Published: December 2020

Background

Polypharmacy is a significant problem of growing interest in healthcare for older adults with the current increase in drug consumption. Inappropriate polypharmacy is a risk factor for numerous adverse health outcomes and creates a growing financial burden to society. Yet, evaluations of objective measures of polypharmacy and their applications in older adults are not well studied. Here, we investigate the medication use in long‐term care residents and their relationships with age and cognition.

Method

Medical records including medication consumption of 350 residents in long‐term care facilities (mean age: 81.1 ± 10.9 years; range: 52–104; female: 63.7%) diagnosed with or without dementia (203:147) were reviewed, using PointClickCare and the InterRAI‐MDS2.0. Four scores assessing medication use were generated at two time points (at baseline and at 12 months or at time of discharge). The drug scores included the counts of 1) total medications, 2) prescription drugs, 3) Beers Criteria drugs, and 4) over the counter medications and supplements. Distributions of each the drug scores were examined and their relationships with age and cognition scores (MMSE) were tested using correlation and regression analyses. Group mean scores were compared for dementia status.

Result

The average number of total drugs, prescription drugs, and beer’s drugs taken were 8.6±4.7 (range: 0‐24), 3.29±5.2 (0‐19), and 1.2±1.2 (0‐6) respectively, and differed by dementia status (p‐value<0.050). Each of the drug scores was related with age (r’s> 0.0685, p‐values<0.050).

Conclusion

Polypharmacy is prevalent in older adults with long‐term care. Residents with dementia have a distinguished profile with medication consumption. Ongoing research in better understanding polypharmacy profiles in relation to frailty and cognition status can further benefit medication optimization of older adults in residential care.
The LUCINDA trial: Leuprolide + cholinesterase inhibition to reduce neurologic decline in Alzheimer's
Authors: Butler Tracy , Atwood Craig S. , Galvin James E. , Maloney Thomas , Glodzik Lidia , de Leon Mony J. , Goldberg Judith D.
Published: December 2020

Background

Leuprolide Acetate has been used for decades to treat hormone‐sensitive conditions such as prostate cancer and endometriosis. In animal models of AD, leuprolide preserves cognition and decreases amyloid deposition and tau phosphorylation by decreasing levels of Luteinizing Hormone. A subgroup analysis of a prior human trial (Bowen, 2016) showed that leuprolide benefited cognition and function in women who were also taking donepezil. Here we describe an ongoing clinical trial of leuprolide to confirm and extend these results.

Method

A three‐site, double‐blind, randomized trial of Leuprolide Acetate (22.5 mg/12 weeks) compared with placebo to evaluate the changes over 48 weeks in cognition, function, brain MRI measures (volume, hippocampal blood flow) and blood biomarkers of inflammation in women (n=150) with mild‐moderate AD who are also taking a stable dose of donepezil. This trial is enrolling at three US sites: Weill Cornell in NYC, University of Miami in Southern FL and University of Wisconsin, Madison.

Result

Results are expected in 2025.

Conclusion

By re‐purposing an existing medication, in combination with a current AD treatment, we will be able to build upon extensive previous research and development efforts, reducing the time frame and costs of making this promising therapy available to patients with AD. Re‐purposing an existing drug likely represents the only realistic option for meeting the HHS goal to “Prevent and Effectively Treat Alzheimer's Disease and Related Dementias by 2025."
The biomarker roadmap for the validation for Alzheimer’s biomarkers: Methodological update for biomarkers of tauopathy
Authors: Boccardi Marina , Dodich Alessandra , Albanese Emiliano , Gayet‐Ageron Angèle , Walter Martin , Rabinovici Gil D. , Carrillo Maria C. , Drzezga Alexander , Hansson Oskar , Nordberg Agneta K , Ossenkoppele Rik , Villemagne Victor L.L. , Teipel Stefan J. , Winblad Bengt , Garibotto Valentina , Frisoni Giovanni B.
Published: December 2020

Background

The 2017 Alzheimer’s disease (AD) Biomarker Roadmap structures the validation of AD diagnostic biomarkers into a systematic sequence of 5 Phases, each encompassing primary and secondary aims assessing analytical validity (Phases 1‐2), clinical validity (Phases 3‐4) and clinical utility (Phase 5). This framework allows us to assess current evidence and identify requirements, gaps, and research priorities towards Phase‐5 validity. While using this methodology to assess the validation status of biomarkers of tau pathology we revised this methodology consistently with progresses in AD research.

Method

First, we critically appraised the adequacy of the 2017 Biomarker Roadmap to assess tau biomarkers and relative to the current biomedical perspective of AD (e.g., A/T/N framework). Second, we proposed and discussed the adaptations at a workshop (Geneva, November 11‐12, 2019) convening the Alzheimer’s Association and 8 leading AD biomarker research groups, tasked with assessing the validity of CSF‐, plasma‐ and imaging‐tau biomarkers for AD according to the updated Biomarker Roadmap framework.

Result

The 2019 updates apply to tau as well as other biomarkers and include: Phase 3: a greater variety of study designs (e.g., cross‐sectional in addition to longitudinal) and reference standards (e.g., AD biomarker confirmation in addition to clinical progression) deemed appropriate to appraise the evidence on tau biomarkers; Phases 1‐5:evidence appraisal examining quality of evidence in addition to target results. Most urgent research priorities for both tau and other biomarkers are to: Define specific clinically‐ and patient‐relevant outcomes with all pertinent stakeholders (patients, caregivers, clinicians, regulators), to prepare proper studies on clinical utility and implementation; Produce/adapt specific reporting guidelines facilitating methodological compliance, reporting and assessment of the produced evidence.

Conclusion

We have revised the Biomarker Roadmap accommodating biomarkers of tau pathology. This revision improves the methodology also for the other AD biomarkers. To further boost their validation up to Phase‐5 studies, the available evidence should be assessed by methodologists not directly involved in the assessed studies, possibly through dynamic data sharing on accessible platforms. Compliance with this methodology is essential to implement tau biomarkers efficiently in clinical research and diagnostics.
The MEMOWAVE project: A phase I/II clinical trial targeting treatment of mild cognitive impairment through sound stimulation during slow‐wave sleep
Authors: Cacciamani Federica , Arnulf Isabelle , Van Quyen Michel Le , Oudiette Delphine , Herreño David Leonardo Henao , Valderrama Mario , Volle Emmanuelle , Epelbaum Stéphane
Published: December 2020

Background

Mild Cognitive Impairment (MCI) is a highly prevalent syndrome especially among the elderly, but its treatment remains challenging. The MEMOWAVE project is a phase I/II randomized, double blind and cross‐over clinical trial. The first objective is to validate the safety and tolerance of a device consisting of a small microphone, also equipped with electroencephalographic electrodes, inserted in the external ear canals. The device produces pink noises during slow‐wave sleep based on real‐time EEG acquisition. The second objective is to investigate the effectiveness of this device in amplifying cerebral slow waves during sleep through sound emission. The third objective is to study the effect of this stimulation on memory consolidation, attention, executive functions, insight, creativity and mood in patients with MCI. Indeed, there is converging evidence that deep slow‐wave sleep plays a major role in these aspects. This process has already shown improvements in memory performance in healthy subjects and during normal aging.

Method

Twenty‐four patients between 40 and 85 years of age will spend three nights in a Center for sleep disorders. Their cognitive functions, insight, creativity abilities and mood will be tested before and after a night of slow wave stimulation or placebo (device in place without stimulation), in a randomized and crossover fashion.

Result

We expect that this device will represent a simple therapeutic approach, easily tolerable by the patient, and able, if successful, of being offered quickly to a larger population of patients with MCI.

Conclusion

We are proposing a new innovative methodology for the treatment of MCI which we are going to test for safety and efficacy.
Therapeutic implications of bio‐algorithm in Alzheimer's disease: Evaluation study
Authors: Mitrasinovic Olivera
Published: December 2020

Background

Understanding Alzheimer's Disease (AD) at the molecular level is prerequisite for successful Diagnostics as well as testing experimental Therapies. Requirements for what are costly materials for many global laboratories have created, in the last two decades, interest in exploring potential of computer technologies, popular Artificial Intelligence (AI) as assisted discovery tool. Despite significant progress, theoretical search for new therapeutics remains under scrutiny. Our study objective was sought to add in the evaluation of its applicability.

Method

In a computer supervised undisclosed‐to‐user study, algorithmic learning task based on modified MatLab platform has been given input data for which experimental laboratory results were known, and program produced output files were subjected to comparative analysis in order to validate their accuracy.

Results

We demonstrate protocol for AI modeling IL‐1α—>IL‐1αR—>MyD88—>TRAF—>IKK—>NFκB signaling pathway that is among main inducers of pro‐inflammation in AD. Rationale for how we introduce standards for normalization iis given. Comparative analysis with experimental laboratory results has showed complete accuracy overlap in mapping signal transducing sequence among interacting factors. Moreover, new protein interactions are identified. Kinetic assay of the IL‐1α/IL‐1αR extracellular binding, as [IL‐1] dose dependent, or over the time course, is feasible for monitoring.

Conclusion

Our results demonstrate collaborative potential of AI‐based methodology as cost‐effective for studies aimed to elucidate mechanism of AD, also early detection screenings and validation tests, while identifying signaling changes among interacting factors may be helpful in predicting clinical outcomes. Ability of the program to monitor kinetic changes is particularly useful for Cytotoxicity assays. Accuracy of AI methodology, dependent on quality of the available data used as input, represents the limitation at the present time. Acknowledgment: Alzheimer's Association, in part.
Association of amyloid load uptake and cerebral blood flow in non‐Alzheimer's disease dementia and mild cognitive impairment
Authors: Chau Anson CM , Cheung Eva YW , Shea Yat Fung , Chiu Patrick Ka‐Chun , Mak Henry , Bao Yiwen
Published: December 2020

Background

Fibrillary beta amyloid deposits and cerebral hypoperfusion are upstream and downstream pathological features in demented individuals respectively. Asymptomatic amyloid plaque deposition begins and becomes saturated way before cerebral structural and metabolic changes in the course of Alzheimer’s disease dementia, and their relationships been vigorously studied. However, the relationship of amyloid load and cerebral functions in non‐AD dementia is under‐investigated. This study aims to investigate the correlation between plaque deposition and cerebral blood flow (CBF) in non‐AD demented individuals.

Method

Thirty‐three non‐AD demented subjects recruited for PET amyloid/MRI study in a University hospital. Each subject underwent a multiparametric MRI brain scanning which included 3D T1W and 2D pseudo‐continuous ASL sequence, and 18F‐Flutametamol Positron Emission Tomography Computed Tomography (PET‐CT). Standardized uptake value ratio (SUVR) of 18F‐flutametamol in eight bilateral cortical regions and absolute CBF of the same regions recorded for each subject. Partial correlation controlling for age between CBF and flutametamol uptake of each brain region computed.

Result

Six non‐amnesic mild cognitive decline (MCI), 14 MCI with vascular pathologies and 13 vascular dementia had SUVR uptake ranged from 0.42 to 0.54, with the most deposition in the occipital, precuneus posterior cingulate (PCC), anterior cingulate, and the least in the prefrontal. Significant mild positive correlations (r=0.3) between SUVR uptake and CBF were found in occipital, anterior cingulate, sensorimotor and prefrontal. Significant moderate positive correlations (r=0.4) were found in temporal lateral and parietal. No significant correlation was found in PCC and temporal mesial.

Conclusion

Increased amyloid deposition in non‐AD dementia and MCI has positive correlation with cerebral blood flow, possibly indicating a different pathophysiological mechanism from AD.
Identification of abnormal astrocyte subpopulation in Alzheimer’s disease
Authors: Jung Yeon‐Joo , Lee Eunbeol , Chung Won‐Suk
Published: December 2020

Background

In Alzheimer’s disease (AD), where amyloid beta (Aβ) plaques accumulate in the brain with surrounding reactive glial cells, synapses are weakened and eliminated. Previously, it was thought that synapse elimination and subsequent neuronal death were mainly due to the direct effects of Aβ oligomers and fibrils on neurons. However, recent studies have revealed that abnormal glial function can be an active inducer of the initiation and progression of AD. Reactive astrocytes are found around Aβ plaques and can internalize Aβ in vitro and in vivo, although the molecular mechanism and biological impact of this clearance are unclear.

Method

We have performed RNA‐seq analysis to reveal the changes of astrocytic gene expression upon oligomeric Aβ exposure. Through this analysis, we have isolated specific genes that are highly upregulated and downregulated in astrocytes during the progression of AD. The expression and function of one of the upregulated genes, KAGS1, are under investigation using APP/PS1 mice.

Result

KAGS1 was detected in APP/PS1 mouse hippocampus starting from 6‐month‐old APP/PS1 mice and its expression was increased in astrocytes along with the progression of AD. We found that KAGS1 was dramatically accumulated in a subset of astrocytes in the hippocampus. Interestingly, organelles with accumulated KAGS1 were co‐localized with p62 and LC3B, indicating that KAGS1 accumulation was associated with autophagy in astrocytes. This dramatic autophagosome accumulation in the aged AD astrocytes appears to be due to the AD related proteasomal as well as lysosomal dysfunctions in astrocytes. Importantly, we found that many critical membrane receptors in astrocytes, such as MEGF10 and LDLR, get trapped inside of the accumulated autophagosomes, instead of localizing in astrocytic membranes.

Conclusion

This finding suggests that the AD astrocytes with accumulated autophagosomes may lose their normal ability for regulating synaptic homeostasis/function and may contribute to AD‐related learning and memory loss.