bluuebunny/crossref_metadata_2025 huggingface dataset:
NIA‐AA AD framework stage 2: Performance in the community
Authors: Petersen Ronald C. , Wiste Heather J. , Machulda Mary M. , Geda Yonas E. , Kremers Walter K. , Therneau Terry M. , Knopman David S. , Mielke Michelle M. , Lowe Val J. , Jack Clifford R. ,   Mayo Clinic Study of Aging
Published: December 2020

Background

The NIA‐AA Research Framework for Alzheimer’s disease (AD) includes consideration of two clinical schemes for staging AD: (1) traditional cognitively unimpaired (CU) to MCI to dementia and (2) a new numeric staging (1‐6) for individuals who are on the Alzheimer’s continuum.

Method

The Mayo Clinic Study of Aging is a population‐based longitudinal study of aging and cognitive impairment in Olmsted County, Minnesota. We analyzed CU persons who had completed three consecutive clinical visits and calculated measures for cross‐sectional categories: objective cognitive impairment and function and measures for change including subjective cognitive impairment (SCD), objective cognitive change (ΔOBJ), and new onset of neurobehavioral symptoms (NBS). We calculated the frequencies for Stage 2 by varying the cutoffs for each of the measures above and assessed stability of this stage over 15 months.

Result

The frequency of Stage 2 varied from 5‐48% depending upon the age of the participants and the cutoff scores used. Membership in Stage 2 required abnormal SCD, ΔOBJ, or ΔNBS and having only ΔOBJ abnormal was the primary reason for inclusion in Stage 2 (45‐62%) followed by 10‐21% having only SCD abnormal. The stability of Stage 2 over 15 months ranged from 31‐65% with 5‐13% progressing to Stage 3 or higher and 22‐43% percent reverting to Stage 1.

Conclusion

Stage 2 was characterized as a transitional period between CU and MCI and could be operationalized with a variety of measures. The staging scheme performed well considering the variables evaluated and cutoff scores employed.
Determinants of cognitive decline and dementia in stage 2: The SCIENCe project
Authors: van Der Flier Wiesje ,   Alzheimer Center Amsterdam
Published: December 2020

Background

We initiated the SCIENCe cohort to study the earliest brain changes leading to Alzheimer’s disease in individuals with subjective cognitive decline (SCD). We aimed to identify which individuals are most likely to progress to dementia using imaging and non‐imaging markers.

Methods

SCIENCe is an ongoing memory clinic cohort, enrolling cognitively normal individuals with SCD. In addition to the standardized diagnostic work‐up (medical exam, neuropsychology, MRI, and lumbar puncture) we offer amyloid PET to participants. Patients are followed annually. Incident dementia was used as outcome. We classified 693 individuals with SCD (60±9yr, 41%F, MMSE 28±2) according to ATN based on CSF, PET and MRI. We measured plasma abeta42/40 ratio with SIMOA. We used Cox proportional hazards models to determine associations with risk of dementia, and to develop prognostic models, providing individualized risks.

Results

Compared to A‐T‐N‐ (56%), participants in the Alzheimer continuum (A+; 18%) had an increased risk of dementia (HR=17, 95%CI 3.6‐79), while the risk in the non‐AD pathologic change profiles (27%) was not increased (HR=3, 95%CI 0.6‐18). Within the A+ profiles, abnormal T and N further increased the risk of dementia. Using Cox regression to develop prognostic models (n=481), we found that the model including CSF biomarkers had a Harrell’s c of 0.82. Using CSF biomarkers, the prognostic model reclassified 58% of individuals with uncertain outcome based on demographics only, as either high or low risk. Finally, in 241 participants with paired CSF and plasma amyloid measurements, we found that both lower CSF abeta42 and lower plasma ab42/40 ratio were associated with steeper rate of cognitive decline. On visual inspection, effect sizes of CSF and plasma amyloid associations with cognitive decline were in the same order of magnitude.

Conclusion

In individuals with SCD, only 18% could be labeled as stage 2 Alzheimer’s disease, based on positive amyloid markers. Those with stage 2 AD are at increased risk of dementia, even more so when there is additional tau pathology and/or neurodegeneration. In the future, it is feasible that biomarkers could be used for individualized risk profiling, and blood based biomarkers could offer a reasonable alternative for CSF and/or PET.
Cognitive and biological characteristics of stage 2 of AD in the clinical multicenter DELCODE Study
Authors: Jessen Frank , Boecker Henning , Buerger Katharina , Heneka Michael T. , Laske Christoph , Peters Oliver , Perneczky Robert , Priller Josef , Schneider Anja , Spottke Annika , Teipel Stefan J. , Wiltfang Jens , Wagner Michael , Düzel Emrah
Published: December 2020

Background

Stage 2 of Alzheimer’s disease holds particular promise for early treatment, because of largely preserved cognitive functioning. Also individuals at stage 2 may contact the medical system due to subjective cognitive (SCD) and potentially mild behavioral symptoms. Current research focuses on the refined symptomatic and biological characterization of stage 2 and the longitudinal cognitive course from stage 2 onwards.

Method

The DZNE (German Center for Neurodegenerative Diseases)‐Longitudinal Cognitive Impairment and Dementia Study (DELCODE) is a memory clinic based project, which enrolled 1078 participants of which 420 were patients with SCD. Extended clinical, cognitive, biomarker and neuroimaging assessments at baseline were performed. Annual follow‐up is ongoing with some having reached the fifth year of observation.

Result

Participants with SCD showed lower concentration of Aß42 in the cerebrospinal fluid and a higher rate of cut‐off‐based amyloid‐positivity. Baseline clinical and biological data, including magnetic resonance imaging (MRI), as well as longitudinal cognitive data of participants fulfilling criteria of stage 2 (SCD and amyloid positivity) will be presented in comparison with data of control subjects, amyloid negative SCD participants, participants with mild cognitive impairment (MCI) and with mild AD dementia.

Conclusion

Stage 2 of AD may be a future target for early treatment. SCD may serve as a clinical indicator of stage 2. DELCODE and other memory clinic‐based studies provide the basis to understand the potential usefulness of stage 2 in clinical trials and clinical practice in the future.
Hyperexcitable PV interneurons render hippocampal microcircuitry vulnerable to amyloid beta
Authors: Hijazi Sara , Heistek Tim , Mansvelder Huibert D. , Smit August B. , van Kesteren Ronald E.
Published: December 2020

Background

Hippocampal Parvalbumin (PV) neurons are GABAergic inhibitory interneurons that provide feedback and feedforward inhibition. They control hippocampal local circuitry and are essential for spatial learning and memory. Accordingly, their dysfunction has been associated with Alzheimer’s disease (AD). Previously, we showed that an early amyloid‐beta dependent PV hyperexcitability is causally involved in hippocampal circuit dysfunction and cognitive impairment in a mouse model of AD. Here, we investigate the short‐ and long‐term effects of PV hyperexcitability on hippocampal function and test whether PV neuron hyperexcitability can render hippocampal circuits vulnerable to amyloid beta.

Method

We use chemogenetics (hM3Dq‐activating receptor with clozapine‐N‐oxide) in order to increase PV neuron activity for three weeks. We then train the mice in the Morris water maze (MWM) in order to asses hippocampus‐dependent spatial memory. Finally, using whole‐cell patch‐clamp recordings, we investigate PV and pyramidal neuron excitability and synaptic transmission in the hippocampus.

Result

We found that prolonged activation of PV neurons disrupts synaptic transmission and causes spatial memory deficits on the short‐term, while on the long‐term, natural compensatory mechanisms restore synaptic transmission and spatial memory. A single low‐dose of amyloid‐beta disrupts long‐term restoration of hippocampal synaptic transmission when PV neurons are hyperexcitable. Specifically, under these conditions, amyloid‐beta impairs PV neuron function, resulting in significant spatial memory deficits.

Conclusion

Taken together, our data show that an induced hyperexcitablity state of PV neurons render hippocampal circuitry vulnerable to amyloid‐beta.
General practitioners’ opinion on early and pre‐dementia diagnosis of AD: A MOPEAD project survey in five European countries
Authors: Sannemann Lena , Müller Theresa , Waterink Lisa , Zwan Marissa D. , Wimo Anders , Stomrud Erik , Pino Susana , Espinosa Jordi Arrufat , Rodriguez‐Gomez Octavio , Benaque Alba , Bon Jaka , Dron Amanda , Ferreira Daniel , Johansson Gunilla , Dumas Annette , Georges Jean , Kramberger Milica G. , Visser Pieter Jelle , Winblad Bengt , Campo Laura , Boada Mercè , Jessen Frank ,   the MOPEAD Consortium
Published: December 2020

Background

Over the last decade, research efforts have facilitated early detection of dementia and underlying diseases, such as Alzheimer disease (AD). There is growing evidence for the benefits of early diagnosis, including access to education, available treatment and support. On the other hand, the lack of a cure and the fear to stigmatize the patient are among the arguments that speak against early disclosure of a diagnosis. General Practitioners (GPs) are often the first contact person when cognitive changes arrive, and they play a key role in early identification of the disease. Based on the experiences working with GPs as part of the multinational “Models of Patient Engagement for Alzheimer's Disease” (MOPEAD) project, an EU‐funded public‐private study within the Innovative Medicines Initiative (IMI‐2) research agenda, we aimed to assess the current attitude of GPs towards early and pre‐dementia diagnosis for AD at the stage of mild cognitive impairment (MCI) or very mild dementia.

Method

We designed a survey to measure the current attitude of GPs towards early and pre‐dementia diagnosis of AD at the MOPEAD sites in five European countries (Germany, Slovenia, Spain, Sweden, and the Netherlands). The questionnaire covered several topics, including attitude towards early diagnosis, diagnostic procedures, resources and opinion on present and future treatment options. Chi‐square tests were carried out to analyze differences among countries.

Result

343 GPs completed the survey. In total, 74% of GPs indicated that they considered an early diagnosis of value. However, only 44% of GPs felt confident in handling the diagnostic procedures for very early dementia and MCI. Currently available pharmacological treatments were mostly regarded as having low benefit, while 68% considered non‐pharmacological treatment options as “beneficial and not sufficiently available”. There were country‐specific differences in the GPs’ perception of monetary resources (X
2(4)=117.26, p < .001) and time (X
2(4)=14.84, p > .01) available for the patient.

Conclusion

Our findings provide an up‐to‐date overview on GPs’ opinion towards early and pre‐dementia diagnosis in five European countries. We show that the majority of GPs considers an early diagnosis beneficial, yet they are faced with country‐specific challenges that can contribute to delayed or missed diagnosis.
Association between social class and cognitive health outcomes in older adults: Systematic review and meta‐analysis of longitudinal studies
Authors: Bodryzlova Yuliya , Belanger Emmanuelle , Moullec Gregory
Published: December 2020

Background

Being born into a given social class still predetermines many aspects of a person’s cognitive biography. People of higher social class have better access to education; to prestigious creative and morally rewarding jobs; and to secure income. Hence, they have better access to two most powerful dementia‐protective factors: life‐long cognitive stimulation and lower level of stress. In this work, we synthetize the association between social class and cognitive health outcomes.

Method

Systematic review and meta‐analysis were conducted. Inclusion criteria were community‐dwelling people age 65 and older; social class as an exposure; dementia, Alzheimer’s disease or cognitive impairment as outcomes; longitudinal observational study as the study design. MEDLINE and Psychinfo databases were used between 01/01/1979 and 07/04/2019. In selected studies, fixed and random effects and homogeneity of effects were calculated. Sensitivity analyses, subgroup analyses and meta‐regression were used to examine sources of heterogeneity and to find possible mediators.

Result

998 abstracts were screened; 38 full‐text articles selected; 8 articles retained in analysis, 3 articles were found in references and 1 article was excluded because it described the same population/outcome. 54 dyads “exposure/outcome” were extracted. Individual (education, income, occupation) and group (neighbourhood) variables were used as indicators of social class. Regardless social class indicator, the pooled RR for dementia/cognitive impairment was 2.45 for fixed effect and 2.18 (95%CI: 2.03 to 2.34) for random effect with I2 heterogeneity of 78%. In sub‐analysis of different social class indicators, the association was strong and homogeneous for income (pooled RR for random effect: 2.07 (95%CI: 1.83 to 2.34), I2: 45%, occupation (RR: 2.53 (95%CI: 2.34 to 2.86), I2=14%) and neighbourhoods (RR: 2.47 (95%CI: 2.33 to2.61), I2=0%). Although education (RR: 2.08 (95%CI: 1.82 to 2.38) had an overall significant association with the cognitive health outcomes, there was a large heterogeneity in the effect (I2=78%).

Conclusion

There is a strong and consistent association between social class and the risk of dementia/cognitive impairment in advanced age. Growing inequality in financial security, favorable workplace conditions and healthy local environments aggravate existing challenges of dementia. Our findings can give insight to policy makers targeting healthy cognitive aging in populations.
Network abnormalities and interneuron dysfunction in Alzheimer’s disease
Authors: Palop Jorge J.
Published: December 2020

Background

Alzheimer’s disease (AD) results in deterioration of cognitive functions and abnormal patterns of neuronal network activity, including network hyperactivity and altered oscillatory rhythms, but the underlying cellular and circuit mechanisms are poorly understood.

Methods

The brain relies on oscillatory rhythms, generated by inhibitory interneurons, to precisely time neuronal firing required for circuit functions.

Results

In this session, we will discuss our recent findings suggesting that interneuron impairment critically contributes to network hyperactivity, altered oscillatory rhythms and cognitive decline in multiple mouse models of AD. We found that oscillatory rhythms reflect behavioural states and strongly modulate network hypersynchrony in mouse models of AD, including including J20 and APP/PS1 mice. Specifically, pathological network hypersynchrony emerges during resting states characterized by decreased gamma oscillatory power and aberrant increases of low‐frequency (12‐20 Hz) oscillatory power. Inhibitory interneuron deficits in AD mouse models are in part mediated by decreased levels of the interneuron‐predominant voltage‐gated sodium channel Nav1.1 subunit. Importantly, restoring Nav1.1 levels and interneuron function by Nav1.1BAC overexpression or interneuron transplants improves interneuron–dependent gamma oscillatory activity, theta‐gamma phase‐amplitude coupling, survival, circadian rhythms and cognitive performance in J20 and APP/PS1 mice, revealing key functional roles for Nav1.1 and inhibitory interneurons. We will also discuss the specific contributions of interneuron cell types such as fast‐spiking (FS, PV) and non‐fast spiking (NFS, SOM) interneurons to generate gamma oscillatory activity and the underlying circuits and cellular mechanisms responsible for altered gamma oscillations in AD mice by optogenetic approaches and multi‐unit and local field potential (LFP) recordings in vivo. Our results suggest that distinct interneurons cell types such as PV and SOM interneurons synergistically cooperate to generate gamma oscillation in vivo and that J20 mice have cell‐type specific functional impairments in this circuit that lead to impaired oscillatory activity. Finally, we will also discuss our translational efforts identifying small molecule Nav1.1 enhancers to increase interneuron function.

Conclusion

Our results highlight the potential therapeutic benefit of restoring inhibitory interneuron function and oscillatory rhythms for cognitive functions and that targeting network dysfunction represents an attractive and complementary therapeutic approach.
The association between tau aggregation and microglia in frontotemporal lobar dementia
Authors: Hartnell Iain James , Blum David , Nicoll James A.R. , Dorothee Guillaume , Boche Delphine
Published: December 2020

Background

Frontotemporal lobar degeneration (FTLD) describes a neurodegenerative disorder caused by protein accumulation in the brain, with the most common form due to aggregated Tau (FTLD‐tau). A potential role for neuroinflammation in FTLD has been highlighted by the discovery of genetic risk variants related to innate/adaptive immunity. Furthermore, studies have shown increased microglial and astrocyte activation together with T cell infiltration in the brain of a mouse tauopathy model (THY‐Tau22).

Methods

To test the possible neuro‐immune interactions in human FTLD‐tau, we obtained FFPE brain tissue from 12 FTLD‐MAPT, 33 Pick’s Disease (PiD) and 45 Progressive Supranuclear Palsy (PSP) patients, as well as 55 controls. Using immunohistochemistry we assessed the tau pathology across diseases using antibodies against several sites of tau phosphorylation in association with phenotypic markers of microglia and T cells.

Results

Our results show that PiD, PSP and FTLD‐MAPT patients had significantly higher phosphorylated tau protein loads (AT8: p<0.001 for all, AT100: p<0.001 PiD & FTLD‐MAPT, p = 0.009 PSP) compared to controls. We also observed a significant correlation between AT8 and AT100 in all but control groups. Whilst no significant changes were seen between groups in microglial markers (Iba1, CD68 and HLA‐DR), significant associations were seen between AT8 and CD68 in control (r=0.389, p<0.004) and PSP cases (r=0.422, p<0.004), with associations between AT100 and CD68 in PiD (r=0.547, p=0.001) and FTLD‐MAPT (r=0.762, p=0.005).

Conclusion

These findings support the involvement of microglia in FTLD, but additional immunophenotyping is necessary for further defining their role in the disease pathogenesis.
The viral protein corona directs viral pathogenesis and amyloid aggregation
Authors: Ezzat Kariem , Malm Tarja , Gustafsson Oskar , Lindén Anders , Andaloussi Samir E.L.
Published: December 2020

Background

Viruses rely on the intracellular host machinery for replication, production of viral proteins and assembly. However, outside cells, as nanosized obligate intracellular pathogens, viruses share many biophysical properties with nanoparticles. Based on this biophysical equivalence, we hypothesized that viruses accumulate a host‐derived protein corona layer in extracellular environments similar to nanoparticles. Also, like nanoparticles, viruses should be able to function as nanosurface catalysts that enable accelerated amyloid protein aggregation extracellularly.

Method

We analyze the protein corona of respiratory syncytial virus (RSV) and herpes simplex virus 1 (HSV‐1) in different biological fluids including human plasma, human bronchoalveolar lavage fluid, non‐human primate plasma, and fetal bovine serum using proteomics, electron microscopy, infectivity and dendritic cell activation assays. In addition, we study the effect of RSV and HSV‐1 on the kinetics of amyloid aggregation of amylodogenic peptides such as amyloid‐beta (Aβ42) peptide, which is the major constituent of amyloid plaques in Alzheimer’s disease (AD) in‐vitro and in‐vivo in AD animal models.

Result

We show that RSV and HSV‐1 accumulate rich protein corona layers that are unique for each biological fluid. Moreover, we show that corona pre‐coating differentially affects viral infectivity and immune cell activation. Additionally, we demonstrate that viruses can bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface‐assisted heterogeneous nucleation. Importantly, we show that HSV‐1, which has been implicated in AD, catalyzes the nucleation and accumulation of the Aβ42 peptide both in‐vitro and in‐vivo.

Conclusion

Our results provide a proof‐of‐concept for the presence of an extensive and dynamic viral protein corona layer that is critical for viral‐host interactions. Unlike the viral genome‐coded surface proteins, the viral protein corona is an acquired structural layer that is dependent on the viral microenvironment resulting in different viral identities based on the target tissue and the target organism. Additionally, the demonstration of corona‐driven heterogeneous nucleation of amyloids illustrates convergence between viral and amyloid pathologies suggesting a direct physical mechanistic link that warrants further investigation. Paper: https://www.nature.com/articles/s41467‐019‐10192‐2.
Human APOE4 carriers show different metabolic signatures than APOE3 carriers throughout Alzheimer’s disease development
Authors: Yanckello Lucille M. , Hammond Tyler C. , Ham Stephanie , Lin Ai‐Ling , Nelson Peter T.
Published: December 2020

Background

Apolipoprotein ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer’s disease (AD). In contrast, ε3 allele of APOE (APOE3), is neutral and doesn’t alter ones risk for AD. As AD is increasingly being viewed as a metabolic disease, the goal of this study was to investigate the metabolic differences between APOE 3/3 or APOE 3/4 in post‐mortem human brain tissue at different stages of AD progression as determined by Braak staging (BS).

Method

Brain samples were obtained from the Alzheimer’s Disease Center Brain Bank at the University of Kentucky Sanders Brown Center on Aging. Samples included APOE 3/3 genotype at BS 0‐3 (n = 64) and 4‐6 (n = 36) and APOE 3/4 genotypes at BS 0‐3 (n = 17) and 4‐6 (n = 41). Samples were sent to Metabolon Inc. to determine metabolic profiles using non‐targeted UPLC‐MS/MS and GC‐MS.

Result

218 Metabolites were detected to be different between genotypes throughout disease progression. More specifically, 179 of the 218 differ between genotypes at BS 0‐3, whereas only 41 were different at BS 4‐6. This shows that APOE genotype differences in metabolism are much more evident in early stages of disease progression. For example, increases were seen in metabolites implicated in oxidative stress such as gamma‐glutamylthreonine in early stage APOE4 carriers compared to non‐carriers. Changes in amino acid and lipid metabolism are also seen in APOE4 carriers early in disease stages, including higher levels of histamine, tryptophan, sphainganine, and sphingadienine. The release of histamine is related to responses to brain disease and altered tryptophan levels have been correlated to intensity of dementia in AD subjects. Altered sphingolipid metabolism has also been found in AD patients.

Conclusion

This study helps shed light on biochemical trends based on AD stage and APOE genotype differences. We found that APOE4 carriers had earlier changes in metabolism related to oxidative stress, amino acid metabolism and lipid metabolism, which all have all been implicated in AD progression. The findings from this study may facilitate future therapeutic development for AD prevention of asymptomatic APOE4 carriers with a precision medicine approach.
Gender differences in the perception of subjective vs. objective cognitive decline: Baseline data from the SCD‐Well Trial
Authors: Meiberth Dix U. , Schild Ann‐Katrin , Sannemann Lena , Müller Theresa , Demnitz‐King Harriet , Whitfield Tim , Schlosser Marco , Krolak Salmon Pierre , Molinuevo Jose Luis , Klimecki Olga , Wirth Miranka , Chetelat Gael , Marchant Natalie L. , Jessen Frank ,   SCD‐WELL Medit‐Ageing Research Group
Published: December 2020

Background

Subjectively experienced cognitive decline (SCD), particularly associated with worries, in older adults is known to be a risk factor for dementia. So far, only few studies focus on gender‐specific profiles in SCD.

Method

Gender differences in SCD subjects who were enrolled in the SCD‐Well trial were analyzed with regard to their perception of subjective cognitive difficulties and the corresponding objective cognitive performance. SCD‐Well is a multicenter, observer‐blinded, randomized, and controlled superiority trial (Marchant et al. 2018). Two different types of 8‐week interventions are compared within the study: a mindfulness‐ and compassion‐based intervention with a validated health education program. 147 participants (95 female) were included. Data from the SCD‐Interview (SCD‐I; Miebach et al., 2019), the Cognitive Difficulties Scale (CDS; McNair & Kahn, 1983), and different cognitive scales summarized in a modified Preclinical Alzheimer’s Cognitive Composite (PACC; Donohue et al., 2014) were analyzed for gender differences.

Result

Statistical analyses revealed no gender differences concerning variables of the SCD‐I and CDS. Regarding objective cognitive performance, a significant gender effect for the PACC score with men showing lower cognitive performance was detected (U = 1859.00 , p < .05). However, only women showed a negative correlation between the PACC and reported SCD as indicated on the SCD‐I (r=‐.436, p= < .001) and CDS (r = ‐.514, p < .001): more subjective cognitive difficulties and worries were associated with lower cognitive performance. To further explore this relationship, we will analyse differences between sites.

Conclusion

Literature reveals gender differences in SCD for objective cognition, neuroimaging and biomarkers (Wang & Tian, 2018). The present study supports the finding of woman performing better in a cognitive assessment than men. Moreover, it adds to this literature by showing an association between self‐perceived cognitive difficulties and actual cognitive performance in women, but not men. Further research is needed to provide a deeper understanding of gender differences in SCD, which are highly relevant for approaches on early detection of cognitive decline, which might in turn impact the choice of pre‐clinical interventions.
Use of the Medtep digital health platform in the framework of a multimodal intervention in patients with subjective cognitive decline (PENSA Study)
Authors: Soldevila‐Domenech Natalia , Forcano Laura , Otero Eduard , Boronat Anna , Lorenzo Thais , Pizarro Nieves , Knezevic Iva , Fauria Karine , Minguillon Carolina , Molinuevo Jose Luis , Panisello‐Royo Josefa M , de la Torre Rafael ,   PENSA Study Group
Published: December 2020

Background

Current evidence suggests that multimodal interventions with diet, physical activity and cognitive training could prevent cognitive decline in individuals at preclinical stages of Alzheimer’s disease. However, maintaining subject compliance is a critical challenge for the success of studies that involve intensive behavioral changes. The PENSA Study is a clinical trial that aims to prevent cognitive decline in 200 older adults (60‐80 years) APOE‐ɛ4 carriers with subjective cognitive decline. A personalized multimodal intervention will combine with a dietary supplement enriched with epigallocatechin gallate (7mg/kg) during 12 months. To continuously monitor the adherence to the intervention and to motivate participants in engaging in healthy promoting behaviors, a digital health platform provided by Medtep has been incorporated in the PENSA Study.

Methods

The Medtep App collects daily information on participant’s diet, mood and social activities using ecological momentary assessments, and registers the attendance to gymnasium, cognitive stimulation and psychoeducational sessions. It also integrates measures of physical activity, heart rate, sleep quality and cognitive performance collected from an activity tracker and a cognitive training telematic platform. Researchers can control the progression of each participant and automatically personalize the intervention according to their characteristics and progression.

Results

During the two weeks prior to the intervention starting date, the information collected is used to establish a reliable lifestyle pre‐treatment measure and to provide each participant with a personalized plan on diet and physical activity. Throughout the intervention, participants receive personalized goals and recommendations, as well as a monthly report with feedback on their behaviors. To this end, several indexes or scores have been created based on participants’ adherence and progression on Mediterranean diet, physical activity, cognition, sleep and social health.

Conclusions

The use of Medtep in the PENSA study is expected to improve participants’ adherence and motivation to the intervention as they might be more aware of what they are expected to do, their strengths and weaknesses, and their progression throughout the study. Furthermore, it will be useful for researchers to track intervention compliance, to make improvements in the intervention throughout the study and to better understand longitudinal changes in behaviors and their impact on cognition.
Hippocampal subfield volume differences are independent of age in teenagers and young adults with Down syndrome
Authors: Koenig Katherine A , Oh Se‐Hong , Stasko Melissa , Lissemore Emma , Roth Elizabeth , Birnbaum Anne , Scheidemantel Thomas , Taylor Hudson , Roizen Nancy , Ruedrich Stephen , Leverenz James B , Costa Alberto
Published: December 2020

Background

Down syndrome (DS) leads to a range of well‐described physiological and neuroanatomical characteristics, including a disproportionate decrease in corrected sizes of the hippocampus [1]. In young adults with DS, we previously reported decreases in the size of bilateral CA1 and dentate gyrus in comparison to age‐matched controls [2]. Here we compare hippocampal subfield volumes in teenagers and young adults with DS to age‐matched healthy controls, and assess the relationship of volume differences to age.

Method

Sample: 34 teenagers and non‐demented adults with DS (mean age (years) 24.5 ± 6.5, range 15‐35; 22 males) and 27 age‐matched healthy controls (HC; mean age (years) 24.9 ± 6.1, range 15‐36; 17 males). MRI: All participants were scanned under an IRB‐approved protocol on a Siemens 7T Magnetom scanner. Using a whole‐brain MP2RAGE (0.75mm3 isotropic voxel size), hippocampal subfield volumes were calculated and corrected for intracranial volume using the Automated Segmentation of Hippocampal Subfields (ASHS) software (Figure 1). Linear regression used to assess group and age differences in the subiculum, CA1, CA3, dentate gyrus, tail and total volumes.

Result

Individuals with DS had disproportionately smaller bilateral CA1, CA3, dentate gyrus, and total hippocampal volumes, all of which were significant for group but not for age (Table 1). Volume of the right tail was the only region that was significantly age‐dependent (0.0039) in the full sample. However, when broken down by group, this relationship was only significant in individuals with DS (r = ‐0.410, p < 0.0168), not in controls (r = ‐0.308, p < 0.1180). In the DS group alone, age did not have a significant effect on any other subfield volume.

Conclusion

In agreement with previous reports, we find a disproportionate decrease in hippocampal volume in persons with DS, driven by CA1, CA3, and the dentate. Although individuals with DS show early neuropathology associated with dementia onset, the majority of subfield volumes were not associated with age in this sample of teenagers and young adults. This work was supported by Alzheimer’s Association, Alana USA Foundation (Contract 200381), and the National Institute of Aging (P30 AG062428 01), with technical support by Siemens Medical Solutions.
Investigating markers of NLRP3 inflammasome activation in neurodegenerative diseases
Authors: Tang Hao , Harte Michael
Published: December 2020

Background

Increasing evidence implicates neuroinflammation in the pathogenesis of various neurological and psychiatric disorders. This is particularly true in neurodegenerative diseases. The NLRP3 inflammasome is a critical component of the innate immune response and its activation is implicated in neurodegenerative disease by emerging studies from both in vitro inflammatory assays and in vivo preclinical models.

Method

Post‐mortem samples were obtained from The Manchester Brain Bank and The Multiple Sclerosis and Parkinson’s Tissue Bank (London). Tissue collections comprised of age and sex matched non‐neurodegenerative controls and Alzheimer’s disease (AD) (temporal lobe; control: Braak stage 0‐II, mild AD: Braak stage III‐IV, severe AD: Braak stage V‐VI. N=40 per group) and Parkinson’s disease (PD) (frontal cortex and substantia nigra, control & PD, N=20 per group per region). Gene expression (mRNA) of NLRP3 and associated proinflammatory markers (AIF1, HLA‐DRA, PYCARD, CASP1, IL1B, IL18 and GFAP), were determined in brain tissues by RT‐qPCR. Aβ42 protein level was assessed in the AD cohort by ELISA.

Results

GFAP (a marker for activated astrocytes) was up‐regulated in severe AD patients compared with controls. This was not significantly related to carriage of the APOE ε4 allele and remained significant in both sex subgroups. Aβ42 protein was upregulated in severe AD group and higher in APOE ε4 carriers. GFAP correlated with Aβ42 but not with the expression of any of the NLRP3‐related proinflammatory markers, which themselves were not significantly changed in the neurodegenerative disease cohorts.

Conclusion

The results indicate that a relative increase in gene expression of the NLRP3 system as an inflammatory marker in neurodegenerative diseases may not be apparent, despite an increase in GFAP in severe AD. Although our data are contrary to previous findings from in vitro and in vivo preclinical studies, they are similar to other two post‐mortem human brain studies. It may be that data from animal models and in vitro studies, in which inflammatory processes are usually generated acutely with abundant stimuli, are not representative of the chronic neuroinflammation associated with neurodegenerative diseases. Future research with greater cell‐specificity and closer examination of protein function in this pathway in well‐characterised human cohorts is urgently needed.
Proteomic analysis of cognitive impairment in responders traumatized by the World Trade Center disaster
Authors: Luft Benjamin , Clouston Sean , Kotov Roman , Bromet Evelyn , Kuan Pei‐Fen
Published: December 2020

Background

WTC responders, particularly those with long‐term PTSD, have an increased incidence of mild cognitive impairment (MCI), a prognostic marker of later dementia. In this study, we used proteomics to interrogate the interaction between PTSD and MCI in a cohort of disaster responders.

Method

The sample included 181 responders to the World Trade Center (WTC) disaster, including 73 with probable PTSD, 61 with MCI, and 81 WTC traumatized controls with neither condition. 34 responders had comorbid PTSD and MCI. PTSD was measured with the Posttraumatic Stress Disorder Checklist (PCL; cut‐point >44). MCI was defined according to NIA‐AA criteria using the Montreal Cognitive Assessment (MoCA; cut‐point <23). In total, we profiled 282 proteins with known involvement in relevant biological processes using the Olink Proseek Multiplex Platform. Specifically, we focused on markers of neurodevelopmental processes, cellular regulation, immunological function, cardiovascular disease, inflammatory processes, neurological diseases. Differential expression analysis was conducted to identify protein biomarkers of PTSD, MCI, and co‐occurring PTSD/MCI.

Results

In total, 46 unique proteins were identified from the combined list of PTSD and MCI associated proteins. Thirty‐seven proteins were differentially expressed in PTSD versus exposed controls at p < 0.05; nine were significant after correcting for multiple comparisons using the false discovery rate (FDR < 0.1). Twenty‐five proteins were differentially expressed in MCI versus exposed controls (p < 0.05); 6 attained an FDR < 0.1. After controlling for PTSD, effect size directions for these 25 MCI‐related proteins were unchanged; 13 remained significant at p < 0.05.

Conclusion

The current study identified several novel protein biomarkers for PTSD and MCI, which were associated with disease burden characterized by co‐occurrence of the phenotypes. Results indicated that half of the proteins associated with PTSD, and vice versa proteins associated with MCI were found in comorbid PTSD and MCI. The results suggest that identification of protein biomarkers might be useful in development of a plasma‐based assay for early detection of MCI in traumatized patients, especially those showing signs of MCI.
Salience network functional connectivity associates with levels of social interactions in healthy and mild cognitively impaired older adults
Authors: Pruitt Patrick J , Damoiseaux Jessica S , Dodge Hiroko H ,   Michigan Alzheimer's Disease Center
Published: December 2020

Background

Older adults are at high risk for both cognitive decline and social isolation. A higher level of social interaction, however, confers a protective effect against cognitive decline, and intervention studies have demonstrated the efficacy of social interactions to enhance cognitive function. The biological mechanism of this enhancement is unclear. Here we evaluate the association between social interaction and the functional connectivity of the salience (SN) and default mode (DMN) networks, two large‐scale brain networks implicated in social and cognitive function.

Method

Michigan Alzheimer's Disease Center at University of Michigan (Ann Arbor, MI, USA) collected data on the Lubben Social Network Scale (LSNS‐6), which indicates levels of social interaction, and resting‐state functional MRI data for 62 older adults with normal cognition (NOR; mean age +/‐ SD = 69.72 years +/‐ 6.24) and 51 mild cognitively impaired (MCI; 71.61 years +/‐ 8.57) participants. We evaluated the association between SN or DMN functional connectivity (DV) and level of social interaction using a linear regression model with age and sex as covariates.

Result

NOR and MCI participants did not differ in age (t=‐1.31, p=0.19), level of social interactions (t=1.47, p=0.14), or SN connectivity (t=1.86,p=0.065), but MCI did have lower DMN connectivity (t=2.839, p=0.005). Level of social interaction associated positively with SN connectivity (t=2.34, p=0.02, rp
=0.218). The Lubben items most strongly associated with SN connectivity were: “How many relatives do you feel at ease with that you can talk about private matters?” (rp
=0.268, p=0.004) and "How many relatives do you feel close to such that you could call on them for help?” (rp
=0.284, p=0.003).

Conclusion

Our data support an association in older adults between greater salience network connectivity and higher levels of social interaction, driven by quality of family interactions. Notably, an association with level of social interaction was not found for default mode network connectivity, suggesting the association found with salience network is not a global network effect. This finding highlights salience network functional connectivity as a meaningful outcome measure for social interventions on cognition in older adults.
COR388, a novel gingipain inhibitor, decreases fragmentation of APOE in the central nervous system of Alzheimer’s disease patients
Authors: Raha Debasish , Broce Sean , Haditsch Ursula , Rodriguez Leo , Ermini Florian , Detke Mike , Kapur Shirin , Hennings Dave , Roth Theresa , Nguyen Mai , Holsinger Leslie J. , Lynch Casey C. , Dominy Steve
Published: December 2020

Background

We identified the bacterial pathogen, Porphyromonas gingivalis (Pg), and its protease virulence factors, gingipains, in the brain of patients with Alzheimer’s disease (AD). Gingipain levels in AD brains were shown to significantly correlate with AD diagnosis and tau and ubiquitin pathology. The neurodegeneration and AD‐like pathology in Pg infected mice were blocked after oral administration of COR388, an orally bioavailable, brain penetrant small‐molecule that irreversibly inhibits lysine‐gingipain. Since ApoE4 is the greatest genetic risk factor for sporadic AD, we investigated if ApoE proteins are targets of gingipain proteolysis.

Method

In vitro proteolysis of recombinant ApoE proteins, Mass Spectrometry (MS) analysis of gingipain cleavage sites, and detection of ApoE proteolytic fragments in brain and CSF.

Result

ApoE proteins were cleaved by gingipains rapidly, and ApoE4 was a preferred substrate over ApoE3. Gingipain inhibitors blocked ApoE proteolysis. MS analysis confirmed higher susceptibility of ApoE4 to gingipain cleavage. MS analysis enabled the identification of cleavage sites and the majority of these sites were concentrated near the carboxy‐terminal of the protein. MS analysis performed on low‐molecular‐weight (LMW) fragments of ApoE4 from a human AD brain, homozygous for the APOE4 allele, identified peptide fragments from this same region. Western blot analysis of AD CSF revealed a higher level of LMW ApoE proteolytic cleavage products in AD CSF than non‐AD CSF. A significant decrease in LMW ApoE fragments in CSF was detected in AD subjects following 28 days of administration of COR388 compared to placebo in a Phase1b clinical study.

Conclusion

Our data suggest that gingipain proteases may mediate ApoE proteolysis in the brain, with higher susceptibility of ApoE4, providing a link between P. gingivalis infection and the APOE4 allele, a major risk factor in AD. Based on the literature, fragmentation of ApoE4 by gingipains would be likely to reduce synaptic maintenance and regulation of immune response as well as aggravate toxicity to cells through the generation of fragments. COR388, a small‐molecule inhibitor of lysine‐gingipain, is currently being tested in a large Phase 2/3 clinical study in subjects with mild‐to‐moderate AD.
Disrupted brain dynamics across the Alzheimer’s disease spectrum is related to tau accumulation
Authors: Botha Hugo , Graff‐Radford Jonathan , Gunter Jeffrey L. , Schwarz Christopher G. , Senjem Matthew L. , Vemuri Prashanthi , Przybelski Scott A. , Wiste Heather J. , Machulda Mary M. , Fields Julie A. , Boeve Bradley F. , Knopman David S. , Petersen Ronald C. , Lowe Val J. , Jack Clifford R. , Jones David T. ,   the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: December 2020

Background

Recent evidence has implicated brain networks in the pathophysiology of Alzheimer’s disease (AD). However, the phenotypic variability in AD, inter‐individual differences in tau PET uptake patterns, and dynamic nature of functional connectivity have been relatively neglected. In this talk, I will discuss our recent work linking measures of dynamic brain organization to spatially independent tau PET patterns defined in a phenotypically diverse cohort.

Methods

We identified all Mayo Clinic participants with concurrent amyloid PET (PiB), tau PET (AV1451) and task‐free fMRI (impaired participants were all Aβ+). We used independent component analysis (ICA) to identify spatially independent patterns of tau PET uptake. For the fMRI data, we used a Hidden‐Markov Model (HMM) design to identify distinct patterns of activity/connectivity (‘states’). The ICA and HMM parameters were used to project/segment an independent cohort (ADNI) and subsequent longitudinal timepoints for the Mayo cohort. Multilevel Bayesian regression models were fit in Stan to explore the association between phenotype, component load and brain state.

Results

The optimal HMM model identified 10 brain states (Figure 1). The optimal ICA decomposition identified 42 tau PET components, of which 13 were potentially related to AD pathobiology (Figure 1). Component loads and brain state dwell time differed between diagnostic groups in both Mayo and ADNI cohorts. One state was much more likely to occur in AD in both cohorts (State 8). Cross‐sectionally, State 8 dwell time was associated with higher tau loads, while higher baseline dwell‐time was predictive of ∆tau in participants with at least 2 timepoints (Figure 2).

Conclusion

We found links between dynamics of functional connectivity, tau deposition, and cognitive impairment across the AD spectrum using two different cohorts and longitudinal data. Specifically: 1) our method for characterizing tau PET uptake was able to capture the magnitude and spatial pattern of binding across diverse phenotypes; 2) Our data supports a role for dynamic brain connectivity in cognitive impairment due to Alzheimer’s disease; 3) Dynamic connectivity appears to be directly related to AD pathobiology as measured by tau PET. Incorporating the time‐varying nature of connectivity will be important in future studies of connectome‐based disease progression in AD.
Apolipoprotein E genotype and the relationship between chitinase 3‐like protein 1 and postoperative delirium: Potential gene‐protein interactions
Authors: Vasunilashorn Sarinnapha M. , Inouye Sharon K. , Ngo Long H. , Fong Tamara G. , Jones Richard N. , Dillon Simon T. , Libermann Towia A. , O'Connor Margaret , Arnold Steven E. , Xie Zhongcong , Marcantonio Edward R.
Published: December 2020

Background

Delirium and Alzheimer’s disease (AD) are common causes of late‐life cognitive impairment with clear epidemiologic links; however, the pathophysiology underlying these links remains unclear. Our recent work suggests that Apolipoprotein E (APOE) ɛ4, the strongest genetic risk marker for AD, does not confer significantly increased risk of delirium in older surgical patients. However, APOE ɛ4 status did modify the relationship of C‐reactive protein (CRP) with delirium, with increased risk for delirium in ɛ4 carriers with high levels of CRP. We now examine whether APOE genotype modifies the established association between inflammatory marker chitinase‐3‐like protein‐1 (CHI3LI/YKL‐40) and postoperative delirium.

Methods

We examined patients without dementia age≥70 undergoing major non‐cardiac surgery in the SAGES: Successful AGing after Elective Surgery study. We collected blood, extracted DNA, and performed APOE genotyping using allele specific polymerase chain reaction assays, considering APOE ɛ4 vs. non‐ɛ4 carriers. Plasma YKL‐40, measured on postoperative day 2 (POD2) by ELISA, was examined using sample‐based quartiles (Q1‐Q4). Delirium status was determined with daily interviews rating the Confusion Assessment Method, augmented by a validated chart review. We used generalized linear models adjusted for age, sex, surgery type, and stratified by APOE ɛ4 carrier status, to determine whether APOE modifies the association between YKL‐40 and delirium.

Results

Among the 557 patients (mean age 76.7 [standard deviation 5.2], 58% female, 81% orthopedic), 19% were APOE ɛ4 carriers. Postoperative delirium occurred in 24%. The YKL‐40‐delirium relationship differed by APOE status. Among APOE non‐ɛ4 carriers, we found a significant relationship between YKL‐40 and delirium (relative risk [RR] (95% confidence interval [CI] for YKL‐40 Q4 vs. Q1: 2.6(1.4‐4.9) and Q3 vs. Q1: 2.3(1.2‐4.5); p‐trend<.01). Among APOE ɛ4 carriers, YKL‐40 was not significantly associated with delirium (RR(95% CI) for YKL‐40 Q4 vs. Q1: 2.0(0.6‐6.6) and Q3 vs. Q1:1.1(0.3‐3.5); p‐trend = 0.37).

Conclusions

APOE non‐ɛ4 carriers may have increased risk of delirium conferred by post‐surgical inflammation specific to the type 2 immune response (high POD2 YKL‐40). These results differ from our prior results with CRP, and raise the intriguing possibility that differing APOE genotypes may interact at different points in the inflammatory pathway leading to delirium.