bluuebunny/crossref_metadata_2025 huggingface dataset:
Tracking the origin of tau spread in the brain
Authors: Jacobs Heidi I.L. , Becker Alex , Kwong Kenneth , d’Oleire Uquillas Federico , Papp Kathryn V. , Properzi Michael J , Rentz Dorene M. , Fakhri Georges El , Sperling Reisa A. , Johnson Keith A.
Published: December 2020

Background

Autopsy studies report that the locus coeruleus (LC) is the first site to accumulate tau, after which it spreads topographically to the entorhinal cortex (EC) and limbic regions. Once tau has reached the cortex, its spread is assumed to occur via connectivity and to be facilitated by Aβ. We aimed to examine whether lower LC integrity is related to tau accumulation in the EC, followed by spreading of tau to cingulate regions. In addition, we examined whether Aβ facilitates tau accumulation beyond these initial regions.

Method

One‐hundred‐and‐five individuals (Figure 1) from the Harvard Aging Brain Study underwent 3T‐MRI (including LC imaging),Aβ and tau‐PET imaging and neuropsychological assessments. Assessments up to 8 years prior to LC‐imaging were included (median:5.02 years). LC intensity (normalized to pontine tegmentum) was regressed onto each vertex of the cortical mantle of the PET data. Robust regressions and mediation analyses related LC intensity to tau, Aβ and cognition (composites and subtests). LME models examined interactions between LC intensity and Aβ on cognitive changes. Covariates were age, sex and education. Results were compared to LME models of tau spread via connectivity in a previously examined extended sample (n=252).

Result

LC intensity was associated with medial and lateral temporal tau (peak:EC (t=4.69)). These associations became more widespread with increasing Aβ (Figure 2). This is consistent with results in the extended sample showing that spread from the EC to the posterior cingulate cortex via structural connections was greater in individuals with elevated Aβ (Figure 3). LC intensity was specifically positively associated with cross‐sectional memory (p=0.024) (Figure 4A‐B) and this was mediated by entorhinal tau (mediation: p=0.007, Figure 4C‐D). Finally, lower LC intensity predicted Aβ‐associated retrospective memory decline (Figure 5, p=0.0009). In the extended sample, lower connectivity and higher downstream‐connected tau accrual was associated with greater prospective memory decline in elevated Aβ persons (Figure 3).

Conclusion

LC intensity measures are associated with initial cortical Alzheimer’s disease (AD) pathology. Elevated Aβ facilitates tau spread to regions outside the medial temporal lobe and accelerates AD‐related cognitive decline. These results mimic autopsy findings of the anatomy of tau spreading and can advance early detection.
Tau spreads through episodic memory networks in the aging brain
Authors: Jagust William J. , Adams Jenna N. , Ziontz Jacob , Cassady Kaitlin , Maass Anne
Published: December 2020

Background

Episodic memory involves an anterior temporal (AT) network specialized for object memory and a posteromedial (PM) network specialized for spatial memory. Tau arises in transentorhinal cortex, in the AT system. These observations suggest that (1) targets of anterolateral entorhinal cortex (alEC) in the AT network should contain more tau than targets of posteromedial entorhinal cortex (pmEC) in the PM network, and (2) patterns of connectivity from the medial temporal lobe may explain tau spread into the medial parietal lobe.

Method

Older cognitively normal participants (mean age 76, sample sizes from 87‐123 depending on the analysis) in the Berkeley Aging Cohort Study (BACS) underwent resting state fMRI on a Siemens 3T Trio system, tau‐PET with [18F]flortaucipir and Aβ PET with [11C]PIB. Young adults (mean age 25, N = 55) were studied with fMRI but not PET. fMRI data was analyzed with seed‐to‐voxel and ROI‐to‐ROI approaches to define networks which were related to protein aggregates measured with PET.

Results

Functional connectivity patterns from alEC and pmEC reflected known AT and PM memory networks. Cortical targets of alEC demonstrated greater tau deposition than targets of pmEC; this effect was greater with higher Aβ and stronger connectivity. Retrosplenial cortex (RSC) showed stronger connectivity to the hippocampus than to alEC or pmEC, and stronger hippocampal‐RSC connectivity was associated with more tau deposition in medial parietal lobe (MPL). Higher hippocampal‐RSC connectivity and more MPL tau associated with poorer episodic memory performance. In comparison to younger individuals, older people showed de‐differentiation of these networks with evidence of alEC aberrantly connected to RSC. Segregation of AT and PM networks, measured as the scaled difference of within‐network correlations minus between‐network connections decreased as tau increased in older adults, reflecting greater functional connectivity between AT and PM networks.

Conclusions

These results indicate that neocortical tau preferentially arises in brain regions strongly connected to alEC as part of the AT system. Aβ potentiation may reflect early AD. MPL tau does not appear to arise directly from entorhinal cortex but from spread via the hippocampus. Functional consequences of these events included reduced network segregation and episodic memory impairment.
Plasma P‐tau immunoassays, methodological aspects and clinical performance
Authors: Blennow Kaj
Published: December 2020

Background

The promise of novel disease‐modifying therapies for Alzheimer’s disease (AD) calls for simple and widely available screening tests for AD‐type pathophysiology, specifically brain amyloidosis (A), tau pathology (T) and neurodegeneration (N). Technical developments have given analytical tools to measure AD protein biomarkers in blood samples. The plasma Aβ42/40 ratio shows high concordance with amyloid PET and blood neurofilament light (NFL) is a sensitive marker for neurodegeneration. CSF P‐tau181 is a well‐established and disease‐specific AD biomarker, but in addition, blood biomarkers for brain tau pathology is urgently needed.

Method

Immunoassays with analytical sensitivity in the low pg/mL range has been developed for P‐tau181 in both plasma and serum samples, with blood levels correlating tightly with corresponding CSF levels in paired samples. Immunoprecipitation mass spectrometry (IP‐MS) experiments verify that the P‐tau181 Simoa assay specifically measure tau phosphorylated at Threonine 181.

Result

Results from several clinical cohorts show that P‐tau181 is markedly increased along the whole AD continuum, from Aβ‐positive cognitively unimpaired elderly to AD dementia cases (p<0.0001). Plasma p‐tau181 also distinguishes AD from other tauopathies and neurodegenerative disorders, e.g. FTD, PSP/CBD, PD and vascular dementia, with AUC values of 83‐100%. Importantly, plasma p‐tau181 is associated with tau (MK‐6240) PET positivity (AUC>90%), but is also increased in the very early phase of AD, in amyloid PET positive but tau PET negative (Braak stage 0) individuals.

Conclusion

Plasma p‐tau181 is a novel promising blood biomarker for AD‐type tau pathophysiology. Blood p‐tau181 may be developed into a simple, cost‐effective and scalable test for screening and diagnosis of AD.
The effectiveness of a self‐administered acupressure intervention in caregivers of Alzheimer's disease patients: A systematic review
Authors: Almeida Jose Roberto , Almeida Maysa Cunha , Cunha Maria Eduarda , Silva Ana Gabriela Correia
Published: December 2020

Background

Caregiving for people with Alzheimer's disease (AD) is highly stressful and has significant negative consequences, such as anxiety and depression. Although a variety of pharmacological and psychosocial interventions have been developed to alleviate caregiver stress, there is a need to find interventions that are effective and acceptable to caregivers. Acupressure, defined as an application of pressure an acupoints using the hands, fingers or thumbs, is a non invasive technique based on the meridian theory of traditional Chinese Medicine (TCM). TCM theory holds that meridians, which are channels in a network of energy pathways through the body, regulate the flow of QI (vital energy) and the unbalanced flow of QI results in disease. By applying external pressure to acupoints and has been successfully used for management of multiple symptoms without adverse effects.

Method

A systematic review was undertaken using the Cochrane library and Medline reporting guidelines. twenty six databases and relevant websites were searched. Two reviewers appraised the quality of the studies and carried out data extraction.

Result

Many studies showed that caregivers are at risk of emotional, mental and physical health problems. Fatigue is often the initial and most difficult problem resulting from the stressful caregiving process and leads to sleep disturbance, anxiety and depression. The emotional and physical strain of caregiving and its adverse impact on family caregivers health and well‐being is recognized as a serious public health problem. Studies have reported positive effects and safety of self‐administration acupressure for this symptoms. This technique has a number of advantages including flexibility, low cost and empowerment.

Conclusion

This results provide evidence for the effectiveness of self‐administered acupressure in reduce stress and improving symptoms of fatigue, insomnia, depression and health‐related quality of life in caregivers of people with AD. It is necessary to provide support to caregivers, to enhance caregivers' feelings of positive emotions. Acupressure may be useful for treatment intervention and thus reduces caregivers anxiety and depression.
Co‐occurring mutations of optineurin (OPTN) and colony‐stimulating factor‐1 receptor (CSF1R) genes in a family with familial frontotemporal dementia
Authors: Yu Jeryl T. , Dominguez Jacqueline C. , Daroy Maria Luisa , Ng Adeline Su Lyn , Tan Yi Jayne
Published: December 2020

Background

We report the clinical profiles and genetics of multiple family members from Samar, Philippines presenting with varying phenotypes of frontotemporal dementia. Literature studies report three gene mutations associated with a majority of fFTD cases, namely the microtubule associated protein tau gene (MAPT), and progranulin gene (PGRN), chromosome 9 open reading frame 72 (C9ORF72). These were all excluded in our case.

Methods

Clinical examination, Cranial MRI, and FDG‐PET were done. Genomic DNA was extracted from blood samples and analyzed via targeted exome sequencing.

Result

A frameshift mutation in the Optineurin (OPTN Chr 10:13166090 G>GA) was identified in multiple family members. This mutation is absent in public large international databases. Clinical and genetic studies show that frontotemporal dementia and motor neuron disease, in particular amyotrophic lateral sclerosis, are part of a disease spectrum with a common pathogenesis. However, there was no clinical or diagnostic evidence of motor neuron disease in family members with Optineurin mutations. A second mutation‐ missense mutation in the Colony‐Stimulating Factor‐1R V235G genes was seen in several family members. Colony‐Stimulating Factor‐1R gene mutations are associated with leukodystrophies when occurring singly. Clinical presentation and diagnostic tests did not support any of these findings.

Conclusion

At present, this is the only reported family with such combined mutations and genotype‐phenotype discordance. We are further investigating this family by conducting whole exome sequencing.
High molecular weight amyloid β1‐42 oligomers induce neurotoxicity via plasma membrane damage
Authors: Yasumoto Taro , Takamura Yusaku , Tsuji Mayumi , Nakayama Takahiro , Imamura Keiko , Inoue Haruhisa , Nakamura Shiro , Inoue Tomio , Kimura Atsushi Michael , Yano Satoshi , Nishijo Hisao , Kiuchi Yuji , Teplow David B. , Ono Kenjiro
Published: December 2020

Background

Amyloid β protein (Aβ) molecules that may contribute to Alzheimer's disease (AD) form low molecular weight (LMW‐Aβ), high molecular weight oligomer (HMW‐Aβ) such as protofibrils, and ultimately fibrils. Recent evidence suggests that oxidative stress and plasma membrane damage induced by soluble Aβ oligomers elicit neurotoxicity and play an initiating role in the development of AD pathology. But the precise mechanisms still remain unclear. In this study, we focused on clarifying the detailed mechanism of the HMW‐Aβ neurotoxicity.

Method

The elution of LMW‐Aβ and HMW‐Aβ was carried out using size exclusion chromatography. SH‐SY5Y cells (Human glioblastoma) were exposed to 5 μM of LMW‐Aβ and HMW‐Aβ for 30 min. To detect cytotoxicity, Aβexposed‐cells were measured mitochondrial activity and release of lactate dehydrogenase. Oxidative stress biomarkers (reactive oxygen species and phospholipid peroxidation of plasma membrane) were assessed. We also assayed intracellular Ca2+ ([Ca2+]i) level and membrane fluidity, and membrane electrical resistance by whole‐cell patch‐clamp.

Result

SH‐SY5Y cells exposed to Aβ oligomers had significantly increased cytotoxicity and oxidative stress compared to untreated cells. The damaging effects of HMW‐Aβ were significantly greater than those of LMW‐Aβ. Exposure of SH‐SY5Y cells to LMW‐Aβ or HMW‐Aβ triggered an elevation in [Ca2+]i. [Ca2+]i levels in SH‐SY5Y cells exposed to HMW‐Aβ rose and maintained high level of [Ca2+]i , while pretreatment with nicardipine and memantine suppressed this continuous rising. Furthermore, both HMW‐Aβ and LMW‐Aβ significantly reduced SH‐SY5Y cell membrane fluidity compared with untreated control cell while, HMW‐Aβ produced a larger decrease in fluidity than did LMW‐Aβ. The resting potential was significantly elevated in SH‐SY5Y cells exposed to HMW‐Aβ compared with untreated control cells and LMW‐Aβ exposed cells and the input resistance was significantly lower following HMW‐Aβ exposure.

Conclusion

These results suggest that HMW‐Aβchanged the structure of lipid bilayer due to cell membrane phospholipid peroxidation and disrupted the homeostasis of ions across the cell membrane. It was speculated that HMW‐Aβ induced neurotoxicity was induced by membrane structural changes such as the formation of small pores in the cell membrane. Accordingly, we propose that the therapeutic reduction of HMW‐Aβ has important implications for the development of AD therapies.
Long longitudinal tract lesion contributes to progression of Alzheimer’s disease
Authors: Xu Yun , Zhao Hui , Luo Cai Mei
Published: December 2020

Background

The pattern of degenerative changes in white matter (WM) microstructure and its relationship with cognitive function have not been clarified yet in the course of Alzheimer’s disease (AD). The present research aimed to explore the alterations of WM microstructure and its relationship with clinical features in amnestic mild cognitive(aMCI) and AD patients.

Method

Neuropsychological data and diffusion tensor imaging (DTI) images were collected from 28 AD subjects, 31 aMCI subjects, and 27 normal controls (NC). Tract‐based spatial statistics (TBSS) were used to investigate fractional anisotropy (FA) and mean diffusivity (MD) among groups. Relationship between diffusion metrics and cognitive functions was examined. A support vector machine (SVM) classification was performed to determine the discriminative ability of DTI metrics in separating aMCI and AD patients from controls.

Result

The values of diffusion metrics in aMCI group presented intermediately between NC and AD groups. As compared to controls or aMCI patients, AD patients displayed widespread WM lesions, including the inferior longitudinal fasciculus, inferior fronto‐occipital fasciculi, superior longitudinal fasciculus and so on. However, no significant FA/MD differences were detected between NC and aMCI groups. Significant relationships between FA/MD metrics of long longitudinal tract and AVLT‐DR scores were found in aMCI and AD groups, respectively. The accuracy of DTI metrics in differentiating controls and AD patients were highly reached 89% and 85% according to SVM.

Conclusion

WM microstructure is extensively disrupted in AD. Long longitudinal tract integrity is closely related to memory and would hold potential value for monitoring the course of Alzheimer's disease.
Hypertension and Alzheimer's disease pathology at autopsy: A systematic review
Authors: Abdulrahman Hanna , den Brok Melina , van Dalen Jan Willem , Richard Edo
Published: December 2020

Background

Hypertension is an important risk factor for all‐cause dementia and Alzheimer’s disease (AD). Reports about the relation between mid‐life hypertension and AD‐related neuropathology are sparse and inconsistent. We conducted a systematic review to collate and synthesize the literature on the relation between hypertension and AD neuropathology.

Methods

Search terms included dementia, Alzheimer’s disease, hypertension, autopsy, obduction and neuropathology. The main outcome was AD‐related neuropathological changes at autopsy (including amyloid plaques and neurofibrillary tangles) with hypertension as exposure, either collected retrospectively from medical records or prospectively measured at clinical evaluation(s). We included prospective and retrospective cohort studies with individuals from general and selected (e.g. memory clinic) populations. We excluded case‐control studies.

Results

We found 10 studies (total N = 3054, median 231 participants, range 50‐1288) that were very heterogeneous concerning populations, methodological approach and statistical analysis. Most studies reported no association between midlife hypertension and AD‐changes at autopsy. Two studies (total n = 1531) reported an association between hypertension and elevated numbers of neurofibrillary tangles and neuritic plaques. Of those studies, one reported that both a low and a high BP in late‐life was associated with an increased burden of amyloid plaques and tangles (U‐shape).

Conclusions

Our study shows no consistent association between blood pressure and AD‐neuropathology. However, based on our results, we speculate that the association between hypertension and AD‐neuropathology is age‐dependent, and that U‐shaped relations may have been obscured in linear analyses. Future studies could take this phenomenon into account when investigating the relation between hypertension and AD neuropathology.
Putative role of β‐arrestin 2 in regulating TNF signalling to NFκB pathway
Authors: Salai Kaung Htet Tun , Lee Jasinda , Dawe Gavin Stewart , Lai Mitchell Kim Peng
Published: December 2020

Background

Neuroinflammation is one of the features observed in neurodegenerative diseases, and inflammatory cytokines and chemokines are two of the important players in the neuroinflammatory responses. β‐arrestin 2 has also been reported to play a crucial role in regulating cytokines and chemokines release as the loss of β‐arrestin 2 leads to an increase in the sepsis‐induced inflammation. However, the role of β‐arrestin 2 in regulating the TNF mediated cytokines and chemokines production is poorly understood.

Method

Stable β‐arrestin 2 knockdown (KD) and negative control (NC) SH‐SY5Y clone cells were used for this study. Subcellular fractionation was used to investigate the cell surface TNF‐R1, and co‐immunoprecipitation (co‐IP) was performed to determine for the possible interaction between TNF‐R1 and β‐arrestin 2. Immunoblotting was used to investigate P65 phosphorylation status. Lastly, cytokines and chemokines mRNA expressions were quantified using Real Time‐PCR after TNF treatment.

Result

Subcellular fractionation showed significantly more TNF‐R1 remained on the cell membrane fraction of KD compared to NC. Using NC cells, co‐IP showed the possible interaction between TNF‐R1 and β‐arrestin 2. KD also demonstrated significant increase in P65 phosphorylation compared to NC, along with significantly higher mRNA expressions of cytokines and chemokines.

Conclusion

These results suggest that prolong TNF‐R1 on the membrane, possibly due to the lack of desensitization by β‐arrestin 2, may have led to an increase in the P65 phosphorylation, and resulting in a significant increase in the cytokines and chemokines mRNA expressions. Hence, our findings established the important role of β‐arrestin 2 in the TNF mediated NFκB pathway, and cytokines and chemokines production.
Race but not sex differences in incidence of dementia diagnosis among older veterans
Authors: Kornblith Erica S , Peltz Carrie , Xia Feng , Barnes Deborah E , Byers Amy L , Yaffe Kristine
Published: December 2020

Background

Although the U.S. military is increasingly diverse, the impact of sex and race on incidence of dementia diagnosis among older Veterans is unknown.

Method

We compared incidence of dementia diagnosis among self‐reported race groups (Non‐Hispanic White, Non‐Hispanic Black, Hispanic, and Asian) and by sex among a random sample of all Veterans > 65 years in the Veterans Health Administration between 10/1/2003 and 9/30/2015. We included Veterans without baseline prevalent dementia (over a 2‐year baseline) with >1 visit during the follow‐up period (< 12 years). Dementia was defined as inpatient/ outpatient diagnoses using International Classification of Disease 9th Edition (ICD‐9) codes recommended by the VA Dementia Steering Committee, dementia medication prescription, or both. We calculated crude incidence by age, sex, and race; and conducted Cox models adjusted for age and sex/race. We further adjusted models for education, income, cardiac/metabolic, and military (post‐traumatic stress disorder, traumatic brain injury) risk factors.

Result

The analytic cohort included 497,127 Veterans (mean age 75.4) after excluding 18,314 with baseline dementia and 11,058 without follow‐up. About eight percent (n=40,352) were diagnosed with dementia during follow‐up. Overall incidence increased by age (50/1000 people, ages 65‐74; 112/1000 for 75‐84, and 116/1000 among 85+; p<0.001). Across all ages, males’ incidence (81/1000) was similar to females’ (77/1000; p=0.10); adjusted Hazard ratio (HR) for females vs. males: 0.96, 95% Confidence Interval (CI) 0.89‐1.03. Hispanic Veterans had highest incidence (154/1000), while Asian veterans had lowest (71/1000); incidence for white Veterans was 79/1000, and 101/1000 for Black Veterans. Compared to white Veterans, Asian Veterans had borderline lower risk of dementia diagnosis (HR: 0.87, 95% CI 0.76‐1.01), and Black (HR: 1.61, 95% CI 1.55‐1.66) and Hispanic Veterans (HR: 1.80, 1.68‐1.93) had increased risk. The pattern of results was similar after full adjustment (Hispanic HR 1.59, 95% CI 1.48‐ 1.71; Black HR 1.49, 95% CI 1.44‐1.54; Asian HR 0.89, 95% CI 0.77‐1.04).

Conclusion

Among older U.S. Veterans, there were differences in incidence of dementia diagnosis by race: Black and Hispanic Veterans had almost two‐fold greater risk compared to white Veterans. Asian Veterans had lower risk. Females and males had similar incidence. These results highlight health disparities requiring further study.
Quality of life scores predict incidence of dementia: Results from PREADViSE
Authors: Ding Xiuhua , Abner Erin L , Schmitt Frederick A , Kryscio Richard J
Published: December 2020

Background

The Medical Outcomes Study Questionnaire Short Form 36 health survey (SF‐36) measures health‐related quality of life (QOL) from the patient’s point of view and is an indicator of overall health status. QOL measures may show differential changes over time prior to dementia onset.

Methods

We analyzed data from the Prevention of Alzheimer’s Disease (AD) by Vitamin E and Selenium (PREADViSE) trial, which recruited 7,547 non‐demented men between 2002 and 2009. A subset of 2,746 PREADViSE participants who completed up to five SF‐36 assessments at annual visits were included in the current analysis. Two summary scores were generated for analysis: physical component score (PCS) and mental component score (MCS), each with a mean 50 with standard deviation of 10. Linear mixed models (LMM) were applied to determine how SF‐36 scores varied over time and by eventual dementia status. Cox proportional hazards regression was used to determine if the baseline SF‐36 scores were associated with dementia incidence, adjusting for baseline age, race, APOE‐4 status, diabetes, and self‐reported memory complaint at baseline.

Results

The mean of MCS at baseline for subjects with dementia diagnosis later (mean± SD: 53.86±9.47) was significantly lower than for subjects without dementia diagnosis (mean± SD: 56.42±6.48) (p = 0.005), while the means of PCS at baseline (Dementia: 49.31±7.93 vs. Non‐dementia: 49.77±7.81) were not significantly different (p = 0.54). The LMM analysis showed a significant effect only for time in PCS. For MCS, the indicator for dementia was significantly associated with poorer self‐reported mental health after adjusting baseline age, black race, and memory complaint. Given adjustments for other risk factors, results from the Cox model showed that a 10‐unit increase in MCS was associated with a 44% decrease in the hazard of a future dementia diagnosis (95% CI: 32%‐55%).

Conclusion

The SF‐36 MCS summary score may be a predictor for future dementia and could be useful in longitudinal dementia research.
Altered Weibull degree distribution in resting‐state functional brain networks in Alzheimer’s disease
Authors: Zhang Yifei , Liao Xuhong , Chen Xiaodan , Liang Xinyuan , Wang Zhijiang , Xie Teng , Wang Xiao , Wang Huali , He Yong
Published: December 2020

Background

The topological organization of human brain networks can be mathematically characterized by the connectivity degree distribution of network nodes. However, there is no clear consensus on whether the topological structure of brain networks follows a power law or other probability distributions, and whether it is disrupted in Alzheimer’s disease(AD) and its prodromal stage, mild cognitive impairment(MCI). We investigated on the fitting of nodal degree distribution of the whole‐brain functional networks and 7 subnetworks in healthy controls(HC) and individuals with MCI and AD.

Method

We included 40 HCs, 34 MCI and 34 early‐stage AD subjects who were recruited from a memory clinic at the Peking University Sixth Hospital. Resting‐state fMRI scans underwent standard preprocessing and were spatially normalized to the standard space. For each subject, we built whole‐brain FC matrices by computing Pearson’s correlations among brain voxels, followed by a threshold process(r from 0.4 to 0.6). Seven pre‐defined subnetworks were obtained from previous studies, including visual, sensorimotor, dorsal attention, ventral attention, limbic, frontoparietal and default mode (DMN). For a given subnetwork, degree distributions were calculated within and between subnetworks, respectively. Maximum likelihood estimation was used to determine model parameters. The goodness of fit of each fitting was evaluated by bootstrapping and the Kolmogorov‐Smirnov test. Group differences in the estimated parameters were tested by ANCOVAs, controlled for age, gender and education.

Result

In the whole‐brain networks and all subnetworks, the connectivity degree distributions were fitted better by a Weibull distribution(f(x)∼x^(β‐1)e^(‐λx^β)) than power law or alternative models. Compared with the HC group, the MCI group showed lower Weibull β parameter (shape factor) in both the whole‐brain and subnetworks, especially in visual, somatomotor and DMN across all threshold(ps<0.05), some of which were distributed in within‐network(somatomotor), between‐networks(dorsal attention and limbic), or both(visual, ventral attention, frontoparietal and DMN). In the AD group, the β parameters were lower in the frontalparietal(p<0.05) and DMN(p<0.05, except for r=0.6) than those in the HC.

Conclusion

We show that the Weibull model fits human brain functional networks better than a power law model, and this network structure is disrupted in AD and MCI. Such a short‐tailed model may capture intrinsic network structure of the human brain in health and disease.
NMDA receptor activation decreases adenosine A2AR function in APPSW,IND animal model of Alzheimer disease
Authors: Navarro Gemma , Reyes Irene , Raïch Iu , Marquez Alejandro Lillo , Del Ser Anna , Casanovas Mireia , Saura Carles , Franco Rafael
Published: December 2020

Background

Etiology of Alzheimer's disease (AD) remain unclear. Different pathological processes have been descrived, such as phosphorylation of tau protein, amyloid plaques, oxidative stress or neuroinflammation. It has been described that over‐activation of the NMDA receptor due to an increase in glutamate levels induces excitotoxicity in neurodegenerative disorders, on the other hand, these disorders course with a chronic neuroinflamation where adenosine A2A receptor play an important role.

Methods

Energy transfer techniques have been assayed to determine protein‐protein interactions. Different signaling pathways have been analyzed, such as MAPK phosphorylation (determined using AlphaScreen®SureFire® kit (Perkin Elmer), calcium release (detected with the GCaMP6 calcium sensor) or Dynamic Mass Redistribution (analyzed by label‐free‐DMR technology). Finally, determination of heteromer expression level has been performed by Proximity ligation assay (PLA).

Result

It has been observed that in LPS activated microglia primary cultures of control mice and also in microglia from APPSw,Ind mice model of AD, NMDA activation inhibit A2AR signalling, decreasing the proinflamatory effects evoked by A2AR stimulation. This inhibition of NMDA receptor over A2AR is characteristic of microglia cells but is only partial in neuronal primary cultures where there is a lower expression of A2A‐NMDA receptor complexes.

Conclusion

NMDA receptor activation decrease the selective A2Areceptor agonist, CGS21680, induced effects in neuronal and microglial primary cultures of APPSw,Indmice model of AD.
Network analysis to identify proteomic markers for brain aging and dementia in healthy older adults
Authors: Short Meghan I. , Zare Habil , Beiser Alexa S. , Larson Martin G. , Vasan Ramachandran S. , Seshadri Sudha
Published: December 2020

Background

Biological processes involved in preclinical stages of Alzheimer’s Disease and Related Dementias (ADRD) are not well understood. The plasma proteome is a promising tool to identify pathways involved in ADRD development, linking genetic and environmental risk factors with disease outcomes. The goal of this study is to leverage proteome data in a community‐based cohort to identify proteins and pathways involved in early stages of dementia. This is the first study to employ a network analysis approach, which can detect subtle but consistent variations in protein expression, to identify biological pathways associated with ADRD and endophenotypes from the plasma proteome.

Method

A panel of 1305 proteins was measured in plasma from 1861 participants from the Framingham Heart Study Offspring cohort (mean age 55, 54% women). Weighted Co‐expression Network Analysis (WGCNA) was used to identify groups (“modules”) of co‐expressed proteins. Summary measures of proteins in the modules (“eigenproteins”) were related to total brain volume (n = 1038), hippocampal volume (n = 1038), and white matter hyperintensity (n = 1022) using linear regression, and incident dementia (128 events, 1740 at risk) and Alzheimer’s Disease (AD; 94 events, 1740 at risk) over 20 years of follow‐up using Cox proportional hazards regression.

Result

Network analysis resulted in 4 modules containing 42, 67, 165, and 272 proteins, respectively. Two modules were associated with total brain volume, one directly (0.17% per standard deviation [SD] increase in eigenprotein; p = 0.005) and one inversely (‐0.26% per SD increase in eigenprotein; p = 1.3 × 10−5). Of these, the first was associated with incident dementia (HR [95% CI]: 0.82 [0.68‐0.99]; p = 0.04), and the second was associated with incident dementia (HR [95% CI]: 1.22 [1.04‐1.44]; p = 0.01), and AD (HR [95% CI]: 1.26 [1.04‐1.52]; p = 0.02). Associations with brain volume remained significant after multiple testing corrections; associations with incident AD and dementia did not. KEGG pathways for axon guidance and cytokine‐cytokine receptor interaction were the most enriched from the two modules, respectively.

Conclusion

Network analysis identified two groups of proteins associated with a brain MRI endophenotype and suggestive of association with incident dementia. These results identify possible biological pathways implicated in early stages of dementia, which we will validate in other cohort studies.
The role of physical activities and clinical risk factors on cognitive reserve: Preliminary results on an Argentine population of older adults
Authors: Feldberg Carolina , Stefani Dorina , Tartaglini María Florencia , Hermida Paula , Garcia Lydia Moya , Somale Maria Veronica , Allegri Ricardo F
Published: December 2020

Background

Lifestyle plays an important role in the way people age. In recent decades, increasing attention has been paid to the role of leisure activities. Evidence from different studies, supports the hypothesis that increased physical activity prevents the onset of cognitive decline. Aerobic exercise has been associated with an increase in cognitive functioning and general wellbeing. The aim of the present study is to analyze if there is a difference in the participation in physical activities between patients with MCI and healthy older adults living in CABA, Argentina.

Method

This was a retrospective comparative study of 145 MCI patients (n= 82) (M=76, 74 years old; ds=6.8 years) and healthy older adults (n=63) (M=71.51 years (ds=8.92) Instruments: Questionnaire of Social Demographic Data (built ad hoc), Questionnaire of Social Participation and an extensive neuropsychological battery that assed memory, attention, language, executive functions and visuospatial abilities was administered.

Results

Results reveal that when comparing the groups, statistically significant differences in favor of the group of healthy older adults were found in their involvement in: swimming (F
(145, 1) = 6.11 p < .001), walking (F
(145, 1) = 18.01 p < .000), aerobic gymnastics (F
(145, 1) = 4.1, p < .05), biking (F
(145, 1) = 3.45, p < .05).

Conclusions

These results agree with other studies which identified the factors that promote healthy cognitive aging in older adults. Within the framework of cognitive reserve, physical activities like: walking, biking, swimming and gymnastics play a differential and important role in the course of cognitive aging. The present study coincides with other researches, and adds empirical evidence of interest for the clinical and scientific fields of healthy cognitive ageing.
Voxel‐based morphometry and resting state fMRI as predictors of neuropsychiatric symptoms in Alzheimer's disease
Authors: Raczek Malgorzata , Cercignani Mara , Banerjee Sube
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) affect most people with Alzheimer’s disease (AD) and have previously been associated with structural and functional brain changes. This study aimed to establish whether there were structural and functional neural correlates that predicted NPS at 3‐year follow‐up.

Method

75 (M=40, F=35) patients who met the diagnostic criteria for AD (N=29), MCI (N=39) and subjective cognitive decline (SCD, N=7) were followed up at 3 years and assessed with Neuropsychiatric Inventory (NPI). T1 and T2*‐weighted EPI MR images were obtained at baseline using the Siemens Avanto 1.5 T scanner for volumetric and resting‐state functional MRI (rs‐fMRI) analysis. Pre‐processing was performed with SPM12 voxel‐based morphometry (VBM) pipeline for the structural imaging and FMRIB software library (FSL) package for the rs‐fMRI. The correlation analysis was performed between the NPS as measured by NPI and the regional brain volume and activity in resting state networks.

Result

Mean age of cohort at baseline was 77 (52‐89). 22 MCI patients converted to AD at 3‐year follow‐up. VBM analysis shows negative correlation with regional brain volume at baseline and presence of neuropsychiatric symptoms (psychosis and affective) at 3 year follow up in people with AD (Figure 1). Brain volumes that correlated negatively with anxiety include anterior/middle cingulate cortex, which has previously been implicated in affective processing and links to default mode network (DMN). Orbitofrontal cortex and cerebellum volumes correlated negatively with high scores in psychosis factor at 3 year f/u. Brain connectivity analysis in participants with AD at f/u (N=41) showed positive correlation of various NPS in default mode (DMN), salience, executive as well as left and right frontoparietal networks( Figure 2 & Figure 3). There was a negative correlation between activity in DMN and appetite.

Conclusion

NPS in AD measured at 3‐year f/u appear to be inversely correlated with regional brain volume and positively correlated with activity in resting state brain networks. Increased activity in DMN and salience networks has previously been associated with psychosis and affective symptoms in other populations.
PBR28 Brain PET imaging with lipopolysaccharide challenge for the study of microglia function in Alzheimer’s disease
Authors: Salardini Arash , Hillmer Ansel T. , Mecca Adam P. , Hashemi‐Aghdam Arsalan , Laltoo Emily , Savoia Sarah , O'Dell Ryan S. , Harris Joanna E. , Godek Tyler A. , Nabulsi Nabeel B. , Lim Keunpoong , Ropchan Jim R. , Huang Yiyun , Cosgrove Kelly , Carson Richard E. , Strittmatter Stephen M , van Dyck Christopher H.
Published: December 2020

Background

The study of neuroimmune function in Alzheimer’s disease (AD) has been challenging, partly because the underlying mechanisms are still incompletely understood. Here we present the results of a novel imaging study in human subjects to assess microglial activity in cognitively normal (CN) participants compared to participants with mild cognitive impairment (MCI) or mild dementia (MD) due to AD.

Method

This pilot study used positron emission tomography (PET) imaging with the radioligand 11C‐PBR28, which is specific for the 18 kDa‐translocator protein (TSPO), a marker sensitive to acute immune effects of lipopolysaccharide (LPS). The 11C‐PBR28 volume of distribution (VT) was measured from two scans, one at baseline and a second at 180 minutes after intravascular administration of lipopolysaccharide (LPS‐ 0.4 ng/Kg). We calculated microglia activation reserve index (MARI) as the proportional increase in binding of 11C‐PBR28, 180 minutes after the administration of the LPS: MARI = [(VT,LPS‐VT,Baseline)/ VT,Baseline] x 100.

Results

CN participants had a significantly higher global cerebral MARI of 35% (SD 13%, n=5) compared to the AD group (MARI=15%, SD 15%, n=5, p=0.030). We found no significant differences between global 11C‐PBR‐28 VT at baseline in CN participants compared to the AD group. MARI values correlated with clinical dementia rating (CDR) ‐ sum of boxes (CDR‐SB) score (R2=0.55, p=0.013), but not with MOCA scores. Conversely baseline 11C‐PBR‐28 VT correlated with MOCA scores (R2=0.44, p=0.025) but not CDR‐SB. TSPO gene polymorphism (high vs. medium affinity binding) did not make a difference in the response pattern. Measurements of serum cytokines indicated that the response differences between the two groups were central and not related to the peripheral immune response.

Conclusion

Our experiment presents preliminary human data on reduced brain microglial activity in AD. Our novel method provides a unique opportunity to test the dynamic response of microglia in vivo. However, further investigations with larger sample sizes are required for better understanding of the role of microglia in AD.
Apolipoprotein E facilitates Aβ oligomer‐induced tau phosphorylation
Authors: Hou Tingting , Du Yi‐feng , Cong Lin
Published: December 2020

Background

Hyperphosphorylated tau is one of the key characteristics of Alzheimer’s disease (AD), and tau pathology correlates with cognitive impairment in AD better than amyloid‐β (Aβ) pathology. Thus, a complete understanding of the relevant factors involved in tau phosphorylation is important for AD treatment. APOEε4, the strongest genetic risk factor for AD, was found to be involved in tau pathology in frontotemporal dementia (FTD). This result indicated that apolipoprotein E (apoE) may also participate in tau phosphorylation in AD.

Method

we injected Aβ oligomer (AβO) into the lateral ventricles of wild‐type (WT) mice and apoE‐/‐ mice to test the process of tau phosphorylation in the acute phase. We also treated cultured apoE‐/‐ neuron with apoE positive and apoE negative medium to test the effect of apoE in Aβ oligomer induced tau phosphorylation press in vitro. Three different isform of apoE were also tested in vitro.

Result

We found that the phosphorylated tau and phosphokinase levels were higher in WT mice than in apoE‐/‐ mice. These phenomena were also confirmed in vitro. ApoEε4‐treated apoE‐/‐ neurons exhibited more phosphorylated tau than apoEε2‐ and apoEε3‐treated neurons. We also found that AβO induced more serious inflammation in WT mice and in apoE‐positive cultured neurons. Anti‐inflammatory treatment reduced the phosphorylated tau level induced by AβOs in apoE‐positive neurons.

Conclusion

These results suggest that apoE may facilitate the phosphorylation of tau induced by AβO via inflammation.
Robotics in dementia: Caregiving needs addressed by an assistive robot in combination with wearable sensors
Authors: Khan Arshia A.
Published: December 2020

Background

Rapid growth in people affected with dementia (PAWD) poses a significant burden in providing care and financial hardship on both the nation’s economy and the affected families. Dementia care expenses are expected to increase to over a trillion by 2050.

Method

The economic and caregiver burden demands solutions to address the growing dementia caregiving needs. I am working with an interdisciplinary team on employing an embedded ethics approach in combining robots, wearable sensors and an intelligent pill‐dispenser to complement human caregiving, specifically, medication management. My project focuses on designing a robotic assistant with special attention to the care needs of women, because two‐thirds of the PAWD, and two‐thirds of caregivers are women, and there is evidence suggesting men experience greater stress than women while providing care. Sensors worn on the wrist of the PAWD, that will track physiological changes, such as blood pressure, blood volume, heart rate variability and electro dermal activity, so that the effects of the medications can be monitored.

Result

The physiological information from the sensors will be transmitted to the robot so when the robot receives a notification from the pillbox alerting to medication time, it will bring medications to the PAWD as well as engage in a conversation, using the information from the sensors. For example, if the sensors indicate a higher blood‐pressure, the robot will discuss this with the PAWD and notify the clinician.

Conclusion

Discussion will focus on existing robotic solutions, end user needs, design considerations, safety and security, and categories of dementia care robots.
Experience with the drug Akatinol memantine in the treatment of early stage dementia of the Alzheimer type
Authors: Tataryan Karine
Published: December 2020

Background

The increase in number of older people makes the study of their health very (actual) topical. The problem of dementia in the first place ‐ dementia, Alzheimer's type, has been steadily growing. This is explained by the frequency of Alzheimer's disease (AD), long debilitating disease course and large economic costs of treatment and care for patients who require lifelong institutionalization for chronically mentally ill. In Armenia, there is still no reliable data on the prevalence of asthma. Low uptake of these patients for psychiatric care leads to low detectability of their psychopathology. Older persons may form a wide range of cognitive impairment ‐ from mild weakening of attention and psychomotor retardation, which are associated with the consequent aging of the nervous tissue and may be regarded as age norm, to the most severe form of cognitive impairment, which is expressed in the development of dementia. In recent years, increasing attention has attracted to an intermediate stage in the development of cognitive impairment when they have not yet reached the degree of dementia, but out of the boundaries of age norms. And it requires special attention and possible preventive measures.

Method

The study included 6 patients with dementia of the Alzheimer type, observation and treatment was carried out at home. The age of patients, respectively, 62, 63, 68, 72, 74, 82. Psychotic disorders they first manifested, ie, it was the first psychotic episode in their lives.

Result

During treatment with small doses of haloperidol, we also used at a dose of memantine Akatinol 10‐30mg/d, 1‐2 times a day for 6 months following the BA, which was subject to fluctuations. As a result, there were improvements in cognitive function, improved attention of patients, short‐term memory tests showed a small, but positive shift, the behavior of patients became calmer. The drug increased concentration and the degree of independence of home patients, thereby reducing the need for care.

Conclusion

This little experience with the drug memantine Akatinol we extend the purpose of identifying significant degree of positive impact of dementia, including Alzheimer's type.
Increased HSC70‐4/HSPA8 regulated autophagy reduces tau‐mediated synaptic dysfunction
Authors: Uytterhoeven Valerie , Deaulmerie Liesbeth , Verstreken Patrik
Published: December 2020

Background

Tau tangles are present in the brains of Alzheimer diseased (AD) patients and strategies that remove Tau oligomers and Tau tangles are tested in clinical trials. These anti‐Tau drugs may keep misfolded Tau from spreading and damaging additional neurons, but they may be inefficient at targeting soluble Tau early in the disease before tangles are formed and thus be relatively late to spare cognitive defects. Our research is therefore refreshing as it may tackle early Tau induced dysfunction. We have shown in Drosophila that the overexpression of the chaperone Hsc70‐4 promotes endosomal microautophagy at presynapses and regulates the turnover of synaptic proteins harboring pentapeptide motifs, biochemically related to the KFERQ sequence (Uytterhoeven, 2015). Intriguingly, Tau harbors two such motifs.

Method

We tested if increasing endosomal microautophagy by overexpressing Hsc70‐4 has an effect on Tau‐mediated synaptic defects .

Result

Indeed, increasing microautophagy reduces presynaptic Tau levels and presynaptic vesicle sequestrations at presynapses, two phenotypes previously shown by our lab to appear after expressing pathogenic Tau in the fly nervous system (Zhou, 2017 and McInnes, 2018). In addition, via lentiviral‐mediated overexpression of HSPA8, the human homologue of Hsc70‐4, we are able to increase HSPA8 regulated autophagy in human neurons.

Conclusion

Together, our work provides important molecular insight into the contribution of Hsc70‐4/HSPA8 regulated autophagy on AD disease onset and progression and may contribute to the development of methods and treatments to alleviate the defects in dementia.