bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of sleep characteristics with mild cognitive impairment and dementia among Chinese elderly people living in a rural area: A population‐based study
Authors: Liu Rui , Tang Shi , Wang Yongxiang , Dong Yi , Hou Tingting , Ren Yifei , Qin Yu , Cong Lin , Qiu Chengxuan , Du Yifeng
Published: December 2020

Background

Sleep patterns might be changed in the early stage of the dementing process. Thus, sleep characteristics may be useful markers for identifying elderly persons at risk of mild cognitive impairment (MCI) and dementia. However, previous studies that investigated the associations of sleep characteristics and cognitive function have been scarcely conducted among Chinese older adults. We aim to determine the associations of various sleep characteristics with MCI and dementia among rural‐dwelling Chinese elderly people.

Method

This population‐based cross‐sectional study included 4680 participants who were aged ≥65 years and living in the rural communities in Yanggu County, Shandong Province. In March‐September 2018, we collected data through interviews, clinical examinations, cognitive testing, and laboratory tests. We used Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale (ESS) to evaluate sleep characteristics such as sleep duration, sleep efficiency, and excessive daytime sleepiness (EDS). Cognitive function was assessed with a neuropsychological test battery. Dementia was diagnosed based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria, and MCI was defined according to the modified Petersen’s criteria. Multiple multinomial logistic regression models were used to examine the associations of sleep characteristics with MCI or dementia.

Result

Of the 4680 participants, 195 were diagnosed with dementia and 691 with MCI. Compare to the sleep duration of 4‐8 hours/night, the multivariable‐adjusted odds ratio (95% confidence interval) of MCI and dementia was 1.34 (1.01, 1.77) and 1.97 (1.25, 3.12) for very short sleep duration (≤4 hours/night), and 1.35 (1.06, 1.72) and 1.74 (1.11, 2.74) for long sleep duration (>8 hours/night). The EDS was significantly associated with the adjusted odds ratio of 1.36 (1.05, 1.78) for MCI and 1.80 (1.15, 2.84) for dementia. Moreover, low sleep efficiency was associated with an adjusted odds ratio of 1.65 (1.18, 2.30) for dementia and 1.10 (0.91, 1.33) for MCI.

Conclusion

Long and very short sleep duration and EDS were associated with an elevated likelihood of MCI and dementia among rural‐dwelling Chinese older adults. In addition, low sleep efficiency was associated with a high likelihood of dementia but not MCI.
Medium‐to‐high physical activity specifically reduces the risk of memory impairment among older adults: The Shanghai Aging Study
Authors: Xiao Zhenxu , Wu Wanqing , Zhao Qianhua , Ding Ding
Published: December 2020

Background

It has been reported that physical activity (PA) could reduce the risk of incident dementia. This study aimed to investigate the relationship between PA intensity and domain‐specific cognitive function among Chinese elderly.

Method

We prospectively followed up 1,373 non‐demented community dwellers aged ≥60 years in the Shanghai Aging Study. At baseline (2009‐2011), a questionnaire was designed to collect their demographic characteristics and PA condition, which was further transformed into metabolic equivalent value (MET). PA was categorized into low (<10.5 METs/week) and medium‐to‐high level (≥10.5 METs/week), based on the tertile of the METs distribution. Participants were administered a battery of neuropsychological tests including 1) Mini‐Mental State Examination (MMSE); 2) Conflicting Instructions Task(CIT) (Go/No Go Task); 3) Stick Test (ST); 4) Modified Common Objects Sorting Test (COST); 5)Auditory Verbal Learning Test (AVLT); 6) Trail‐making Tests A and B;7) Modified Common Objects Sorting Test (HOMT); and 8) Renminbi (currency of China) Test. Participants with <6 years of education were given tests 1 to 4, 7 and 8. Participants with ≥6 years of education were given tests 1 to 6. At the follow‐up (2014‐ 2016), same neuropsychological battery was used to evaluated the domain‐specific cognitive functions. Impairment of each domain was defined as having test score >1Standard Deviation (SD) worse than that of baseline. Cox regression model was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for cognitive impairment of each domain in two PA levels.

Result

There is significant difference of incident cognitive domain impairment between low and medium‐to‐high PA groups in MMSE (p<0.001), Go/No‐Go correct tapping (p=0.029) of CIT, imitating (p=0.003) of ST, delayed recall (p=0.034) and recognition (p=0.005) of AVLT/HOMT. After adjusted for age, sex, education year, APOE ε4, smoking, drinking, hypertension, diabetes and body mass index, participants with medium‐to‐high baseline PA had a lower risk of impairment in MMSE (HR 0.45, 95%, CI 0.31‐0.66), delayed recall (HR 0.54, 95% CI 0.34‐0.87) and recognition (HR 0.58, 95% CI 0.34‐0.98) of AVLT/ HOMT.

Conclusion

Medium‐to‐high level of PA was independently associated with reduced risk of global cognition and memory impairment in older adults.
Effect of berries and fruits on cognitive change during a 2‐year multi‐domain lifestyle intervention: The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER)
Authors: Eskelinen Marjo H , Solomon Alina , Ngandu Tiia , Antikainen Riitta , Hänninen Tuomo , Laatikainen Tiina , Lindstrom Jaana , Paajanen Teemu , Soininen Hilkka , Strandberg Timo , Tuomilehto Jaakko , Kivipelto Miia , Lehtisalo Jenni ,   FINGER Study Group
Published: December 2020

Background

Dietary components such as berries and fruits are part of the recommended Nordic diet, and are considered having health‐enhancing characteristics. A randomized multi‐center and multi‐domain lifestyle intervention trial FINGER has shown benefits on cognition with dietary guidance, exercise, cognitive training and vascular risk management. Here, we investigate the association between berry and fruit intake at baseline and cognitive function over 2 years.

Methods

Individuals aged 60‐77 years were randomly assigned in a 1:1 ratio to intervention (n=631, nutritional guidance, exercise, cognitive training, and management of metabolic and vascular risk factors) or control group (n=629, general health advice). A modified neuropsychological test battery and 3‐day food records were administered annually. Mixed‐model repeated‐measures analyses with maximum likelihood estimation were used to analyse change in cognitive scores as a function of randomization group, time, berry consumption, total energy intake, berry consumption x time interaction, group x time interaction, energy intake x time interaction, age x time interaction, age, sex, education, study site, C‐reactive protein, systolic blood pressure, and low‐density lipoprotein cholesterol. A similar model was used to investigate effects of fruit consumption.

Results

High berry consumption at baseline compared with no berry consumption was associated with more improvement in all investigated cognitive domains. Berry consumption x time interaction coefficient (95% CI) was for global cognition 0.058 (0.034‐0.082), p<0.001; for executive functioning 0.050 (0.018‐0.081), p=0.002; for memory 0.069 (0.028‐0.109), p=0.001; and for processing speed 0.051 (0.018‐0.085), p=0.003 over two years. When berry consumption was combined with fruit consumption, the results remained similar. However, fruit consumption alone did not show any association with the cognitive domains.

Conclusions

Berries are an important component of the Nordic diet, and higher consumption of berries seems to have a beneficial impact on cognitive functioning. Several healthy components such as flavonoids in berries might be behind this association, e.g. by influencing cerebrovascular blood flow and synaptic plasticity of the brain. Acknowledgements: The presenting author wish to acknowledge The Juho Vainio Foundation; Yrjö Jahnsson Foundation; Päivikki and Sakari Sohlberg Foundation.
Large‐scale analysis of heart‐brain interactions through personalisation of a mechanistic cardiovascular model
Authors: Banus Jaume , Lorenzi Marco , Camara Oscar , Sermesant Maxime
Published: December 2020

Background

Heart and brain are linked by means of pathophysiological and physiological mechanisms sharing several risk factors (Doehner, W. et al. 2018). Clinical evidence supports a common underlying cardiovascular pathophysiology relating cardiac function and brain damage (Moroni, F. et al. 2018). Nevertheless, heart and brain have usually been studied independently and until now the lack of databases combining data from both has prevented to properly study their relationship. Computational cardiovascular models can complement statistics imposing prior knowledge using a mechanistic approach, and can help us to estimate non‐observable parameters key for the cardiac function such as cardiac contractility or aortic compliance, which cannot be measured in‐vivo.

Method

extending the approach presented in (Mollero, R. et al. 2018) we propose to constrain the personalisation of a cardiovascular model to ccount for the relationships between cardio‐vascular parameters and brain‐volumetric features extracted from imaging data. We applied our framework in a cohort of more than 3400 subjects and in a pathological subgroup of 59 subjects diagnosed with atrial fibrillation (AF).

Results

We observed an association between non‐observable parameters such as aortic stiffness or peripheral resistance with brain‐volumetric features such as white matter hyperintensities (WMH) and brain ventricles volume. Moreover, we observed differences in the estimated parameters between AF subjects and control groups linking AF with WMH and cardiac remodeling (Seko, Y. et al. 2018).

Conclusion

Our methodology allows to study the influence of the brain features in the estimation of the cardiac function parameters, and to identify significant differences associated to specific clinical conditions, such as between atrial fibrillation and white matter damage.
Integrated dementia care centers in Southern Taiwan: Experiences from Chi Mei Medical Center
Authors: Chou Chih‐Ho
Published: December 2020

Background

Taiwan is facing a social crisis of super‐aged society. In response to the increasing burden, Taiwan launched the Dementia Plan and Action Plan 2.0, which is a part of Long‐term Care Service Network in 2018. The integrated Dementia Care Centers (IDCC) and Support Centers for People with Dementia and their Families (SPDF) were funded under this plan. We reported the executive experiences of IDCC and SPDF in our institution.

Method

We recruited patients with mild to moderate dementia or diagnosed MCI from (1) who received ambulatory care from our hospital and (2) who was referred from neighborhood hospital/clinics. Patients with severe medical comorbidities or disability were excluded. We analyzed those received follow‐up for more than 12 month or died within the period. Age, gender, clinical diagnosis, education, baseline cognitive assessment, dementia severity (CDR), medical treatments, behavior and psychological symptoms(BPSD), long‐term care services usage, 12‐month‐follow‐up cognitive assessment and CDR were analyzed.

Result

We recruited 453 subjects in the first year. Among the recruited patients, 121 women and 72 men completed 12‐month follow‐up. The average age was79.2 (SD=8.4) in women, and 80.0(+7.5) in men respectively. Moderate or above disease severity was more common among in women. Low educational level was more in women than men (57.9% vs 22.2%). Alzheimer’s disease (AD)was the most common diagnosis. Thirty‐six patients had a least one documented BPSD or took antipsychotic agents during the observation period. Most patients at mild to moderate stages, the primary caregiver were their spouses or offspring. More than a half of severe patients needed to hire a foreign caregiver. Only 25.2% patients requested long‐term care services. The most commonly used service were day‐care facilities.

Conclusion

Our analysis demonstrated that senility and late diagnosis were still challenging in Taiwan society. The causes of low utilization of long‐term care services were quite diverse and heterogeneous among geographical regions. How to reduce the caregiver burden and improve the efficiency of long‐term care services needs further optimization and communication.
Venular amyloid and its relationship with cerebral amyloid angiopathy in TGF344AD rats
Authors: Bishay Jossana , Beckett Tina , Lai Aaron Y. , Hill Mary E. , McMahon Dallan , Simpson Craig , Hynynen Kullervo , McLaurin JoAnne
Published: December 2020

Background

In Alzheimer’s Disease (AD), the amyloid‐beta peptide (Aβ) aggregates and deposits in the form of amyloid plaques within the brain parenchyma. Overproduction of Aβ is less common in sporadic AD cases, suggesting that impairment in Aβ clearance contributes to disease pathology. In AD, failure of the perivascular drainage pathway leads to Aβ deposition in the walls of cerebral blood vessels, resulting in cerebral amyloid angiopathy (CAA). The association between amyloid deposits with arterioles and capillaries is known, however, amyloid deposits present in venules is still controversial.

Method

A TgF344‐AD rat model overexpressing the human APPswe and PS1ΔE9 mutations was used as it recapitulates the typical hallmarks of AD in humans, including Aβ plaque formation, CAA, tau pathology, frank neuronal loss, and cognitive deficits. At 7, 10, 13, and 16 months of age, brain sections were examined by immunofluorescence staining and image analyses for amyloid deposits around all blood vessels using Thioflavin S staining. Further identification of deposits with Aβ specific antibodies, 4G8 (17‐28), MOAB2 (1‐4), and anti‐Aβ1‐40/42, were used to confirm Thioflavin results. Amyloid aggregates were isolated from parenchymal plaques, CAA, and venular amyloid using a laser capture microdissection (LCM) microscope and sent for mass‐spectrometry (MS) to identify the presence of Aβ.

Result

Results suggest as an increase in CAA is detected, venular amyloid starts to accumulate, with disease progression. Confirmation with antibodies that span the Aβ sequence, 4G8, MOAB2, anti‐Aβ1‐40/42, identify amyloid deposits in both venules and arterioles. Furthermore, LCM‐MS technique identified presence of Aβ in cortical plaques and CAA samples.

Conclusion

Correlation with venular amyloid deposition and CAA suggests an important interplay between these vascular pathologies with AD progression. Understanding venular amyloid and its relationship with CAA can play a role in studying mechanisms involved in neurovascular dysfunction of AD.
Alzheimer’s disease‐related necroptotic pathology: An exclusive presence of the necrosome in granulovacuolar degeneration inclusions in human and transgenic mouse brains
Authors: Koper Marta J. , Van Schoor Evelien , Ospitalieri Simona , Vandenberghe Rik , Vandenbulcke Mathieu , von Arnim Christine , Tousseyn Thomas , Reichwald Julia , Rabe Sabine , Staufenbiel Matthias , Balusu Sriram , De Strooper Bart , Thal Dietmar Rudolf
Published: December 2020

Background

Alzheimer’s disease (AD) is characterized by pathological processes such as β‐amyloid (Aβ) plaques, neurofibrillary tangles (NFT), cytoplasmic granulovacuolar degeneration (GVD) lesions and neuronal loss that underpin cognitiveand behavioral alterations. Necroptosis, a programmed form of cell death defined by the assembly of the necrosome complex composed of phosphorylated proteins (pRIPK1, pRIPK3 and pMLKL), has recently been shown to be involved in AD.

Method

To determine the neuropathological characteristics and distribution pattern of the necrosome components, we performed a comprehensive immunohistochemical analysis of brains of AD, pathologically defined preclinical AD and non‐AD control cases. A similar analysis was carried out to investigate necroptosis‐related proteins in transgenic mouse models of Aβ and Tau pathology.

Results

We identified all three activated necrosome components (pRIPK1, pRIPK3 and pMLKL) in GVD inclusionswithin neurons of the hippocampal subfields CA1, CA2/3, CA4, dentate gyrus, subiculum, entorhinal cortex, temporal cortex, hypothalamus, amygdala and frontal cortex of symptomatic and preclinical AD patients. The three necrosome proteins colocalized with standard GVD markers, such as pTDP‐43 and CK1δ, and similarly to these markers detected GVD lesions. Necrosome‐associated GVD neurons inversely correlated with neuronal density in the early affected hippocampus and in the late affected frontal cortex. Necroptosis‐specific GVD lesions showed strong positive associations with AD‐defining parameters, showing the strongest correlation and partial colocalization with Tau pathology. Moreover, we analyzed brain tissues of transgenic mice carrying mutated APP, Tau or both transgenes. We found morphologically comparable GVD lesions positive for the necroptosis components in the subiculum, hippocampus and entorhinal cortex of 12‐month‐old APP23xTAU58 mice. We confirmed mouse necrosome‐positive GVD inclusions by CK1δ immunoreactivity.

Conclusion

The presence of the necrosome in GVD inclusions points to a specific form of necroptosis in AD that can be modelled in APPxTAU transgenic mice, possibly indicating Tau and/or Aβ as drivers of this pathology. Necrosome‐positive GVD granules represent a potential protective system sequestering the necrosome complex, which could interfere with or delay necroptosis‐related neuronal death.
Effects of a liver APOEε4‐genotype on synaptic integrity, gliosis and insulin signaling in the brain
Authors: Giannisis Andreas , Patra Kalicharan , Edlund Anna K. , Rosa Andrés De La , Nieto Lur Agirrezabala , Gras Joan Benedicto , Moussaud Simon , Bengtsson Tore , Fu Yuan , Bu Guojun , Bial Greg , Foquet Lander , Hammarstedt Christina , Strom Stephen , Kannisto Kristina , Ellis Ewa , Nielsen Henrietta M.
Published: December 2020

Background

APOEε4 is the strongest genetic risk factor for AD[1]. Although plasma apoE does not cross the blood‐brain‐barrier[2], altered plasma apoE levels have been linked to increased risk of AD[3] and to unfavorable CSF Aβ42 and tau levels[4]. Translation of results from studies of apoE in rodents to the human situation is difficult due species‐specific difference for instance in lipid metabolism[5]. Here we have studied the effects of a humanized APOEε4 liver[6] on synaptic integrity, insulin signaling and gliosis in a mouse model that reproduces the human plasma profile and that retains its endogenous apoE expression in the brain.

Method

Tissue samples from the cortex, hippocampus, cerebellum and thalamus were obtained from FRGN mice with humanized APOEε2/ε3 (n=4) versus APOEε4/ε4 (n=8) livers, and from APOEε3/ε3 (n=3) and APOEε4/ε4 (n=3) TR mice. Using established protocols[7], nuclei‐ and synaptosome‐enriched, and synaptosome‐depleted fractions were generated and analyzed for contents of markers relating to synapse integrity, gliosis and insulin signaling using western blotting. Levels of apoE4 were assessed in plasma from FRGN mice with humanized APOEε4/ε4 livers.

Result

Cortical and hippocampal levels of endogenous apoE, cortical levels of tubulin‐βIII, AMPAR, NMDAR, bassoon, mTOR, pAkt and a‐synuclein as well as hippocampal levels of synaptophysin, EAAT2, GFAP, NMDAR, pmTORS2448 and pIRS616 were reduced in FRGN mice with humanized APOEε4/ε4 versus APOEε2/ε3 livers (p≤0.05). Several of these findings were recapitulated in brain tissues from APOEε4/ε4 versus APOEε3/ε3 TR mice (p≤0.05). In both mouse models we observed a shift of a‐synuclein content from the synaptosomal (reduction) to the extra‐synaptosomal (increase) compartment (p<0.05). Altered expression levels of synaptic markers were also found in the thalamus and to a lesser extent in the cerebellum. Plasma levels of apoE appeared lower in the humanized APOEε4/ε4 liver mice and correlated positively to cortical levels of endogenous apoE but negatively to various markers of synaptic integrity and insulin signaling mainly in the hippocampus.

Conclusion

We here provide the first evidence of a profound and negative effect of a liver APOEε4 phenotype in a human‐like setting, on key markers related to brain synaptic integrity, insulin signaling and glial cells involved in neuroinflammation.
Strategic corpus callosum lesions are associated with worse cognitive performance in cerebral amyloid angiopathy
Authors: Freeze Whitney M. , Zotin Maria Clara Zanon , Warren Andrew D. , van der Weerd Louise , Gurol M. Edip , Viswanathan Anand , Greenberg Steven M , Reijmer Yael D. , van Veluw Susanne J.
Published: December 2020

Background

Cerebral amyloid angiopathy (CAA) is highly prevalent in Alzheimer’s disease (AD) and is associated with hemorrhagic and ischemic brain lesions. CAA is increasingly recognized as an important independent cause of cognitive impairment. However, the mechanisms underlying cognitive impairment in these patients are poorly understood. We hypothesized that lesions in the corpus callosum (CC), because of their strategic location, are associated with widespread reductions in microstructural white matter integrity and worse cognitive performance, specifically in the domains of attention/information processing speed and executive functioning.

Method

57 individuals meeting the modified Boston criteria for probable CAA underwent 3T MRI, including a DTI scan, and neuropsychological testing. Microstructural white matter integrity was quantified by means of fractional anisotropy and mean diffusivity. Test scores on individual neuropsychological tests were converted into Z‐scores and averaged into the following cognitive domains: memory, attention/information processing speed, language, executive functioning, and visuospatial processing. CC lesions were defined as hemorrhagic (microbleeds or larger bleeds) and ischemic (microinfarcts, lacunar infarcts, and FLAIR hyperintensities). Associations between CC lesion presence, microstructural white matter integrity, and cognitive performance were examined with multiple regression models, corrected for age, sex, education (when cognition was the dependent variable), and history of large ICH. False discovery rate corrections for multiple comparisons were applied.

Result

Demographic and imaging characteristics of cases with and without CC lesions are outlined in table 1. Sixteen cases (28%) had one or two CC lesions (n=18 lesions). Most lesions were located in the splenium (n=8), followed by the genu (n=7) and the midbody (n=3) of the CC. In multivariate regression models, presence of CC lesions was associated with reduced microstructural white matter integrity on DTI within the CC and in the total white matter. Interestingly, cases with CC lesions performed significantly worse on the domains of attention/information processing speed, and executive functioning compared to those without CC lesions, but no differences were found for the other domains (table 2).

Conclusion

Because of their strategic location, focal CC lesions may significantly contribute to cognitive impairment in CAA, potentially through their negative impact on the microstructural white matter integrity beyond the lesion core (i.e., Wallerian degeneration).
An ABCA7 partial deletion and a GRN variant in a semantic variant of primary progressive aphasia patient
Authors: Antonell Anna , Ramos‐Campoy Oscar , Balasa Mircea , Borrego‐Écija Sergi , Montagut Núria , Falgàs Neus , Tort‐Merino Adrià , Olives Jaume , Fernández‐Villullas Guadalupe , Bosch Beatriz , Sanchez‐Valle Raquel , Lladó Albert
Published: December 2020

Background

ABCA7 gene (ATP‐binding cassette transporter A7) loss‐of‐function mutations are related to increased risk of suffering Alzheimer’s disease (AD). On the other hand, mutations in GRN (Progranulin) gene are causative of frontotemporal dementia (FTD).

Methods

The proband was a patient diagnosed from semantic variant of primary progressive aphasia. Age at onset was at 50 years‐old, presenting progressive cognitive decline with an important language loss. The MRI showed a left temporal atrophy. AD CSF biomarkers were normal and no familial history of dementia was reported. Next generation sequencing was performed with Illumina NextSeq500. Single nucleotide variants were detected using GATK and copy number variants using ExomeDepth algorithm. Sanger sequencing was performed for GRN variant confirmation and MLPA technique for ABCA7 deletion validation. C9orf72 repeat expansion was studied with a repeat primed PCR and fragment analysis. Biological samples from his mother and a brother were obtained. Commercial ELISA kit was used to measure serum PGRN levels (Adipogen).

Results

Patient showed an ABCA7 partial deletion (exons 17‐47) plus 4 contiguous genes, of a total of 105 kb in size (hg19 chr19:g.1048865_1154298). Deletion was confirmed in the proband and discarded in the proband’s mother and brother by MLPA. Patient and his mother (asymptomatic at 81 yo) were also carriers of a reported GRN variant, p.(Asp33Glu; rs63750742). Progranulin serum levels were normal in the patient and his family members. C9orf72 screening was negative.

Conclusions

The patient harbored two genetic alterations in genes related to dementia risk, although it is unlikely that any of them alone could be responsible of the FTD phenotype. ABCA7 deletion should be de novo or father inherited. ABCA7 protein truncating variant at exon 14 (p.Arg578fs), which has a similar protein consequence, is relatively frequent in control population, although has showed a 1.8‐fold enrichment in AD patients. Moreover, GRN variant does not seem to be pathogenic or low penetrance because proband’s mother is unaffected and serum progranulin levels are normal. In conclusion, these variants per se are likely not sufficient to cause the disease, but rather risk variants of intermediate to high penetrance along with other factors.
Functional ultrasound imaging can detect vascular changes in tau P301S mouse model of Alzheimer’s disease
Authors: Rytkönen Jussi , Shatillo Artem , Dudek Mateusz , Puoliväli Jukka , Oksman Juho , Parkkari Teija , Miszczuk Diana , Yang Cindy , Braithwaite Steven P , Minami S. Sakura
Published: December 2020

Background

Tauopathies are neurodegenerative disorders characterized by the accumulation of abnormal tau protein leading to cognitive and/or motor dysfunction. Evidence suggests that tauopathy mouse models develop changes in blood vessel morphology, density and altered cerebral blood flow, which could be linked to cognitive deficits in Alzheimer’s Disease. Here we assess changes in neurovascular coupling in Tau P301S mouse model (MAPT P301S, PS19) using functional ultrasound (fUS) and its relationship to histological changes and cognitive deficits.

Method

Hemizygous (HE) P301S mice and their wild type littermates (n=20) were used in the study. fUS imaging of the brain was performed at 6 and 7 months of age, including resting state functional connectivity (RFC), somatosensory stimulation and acetazolamide challenge (ACZ, 30 mg/kg). At 7 months contextual fear conditioning (CFC) and radial arm water maze (RAWM) tests were used to assess behavioral impairments. At study end, brains were histologically assessed for microgliosis and synaptic density.

Result

At 6 months of age, fUS imaging showed differences between genotypes in all measurements. Resting state imaging showed a reduction in RFC of sensory‐motor cortex of HE animals. Chemical stimulation showed strong vascular reaction in HE mice after ACZ challenge. Somatosensory stimulation resulted in lower response in HE mice compared to WT. The fUS data at 7 months had a lower signal‐to‐noise ratio compared to 6 months, but similar trends were observed. In RAWM HE mice made less errors and displayed a trend toward increased latency in finding the platform compared to WT. The progression pattern of HE animals during CFC differed from WT counterparts. Significant increases in microgliosis by CD68 immunostaining were observed in HE mice, accompanied by a significant reduction in synapse density.

Conclusion

fUS is a powerful tool for functional imaging of preclinical CNS disease models. Here we confirmed vascular changes in P301S mouse model accompanied by mild decline in cognition and significant effects on neuroinflammation and synaptic density.
Frailty as a risk factor for incident dementia and cognitive decline: Data from the longitudinal InveCe.Ab study
Authors: Davin Annalisa , Cereda Cristina , Ardemagni Deborah , Mimmi Maria Chiara , Abbondanza Simona , Vaccaro Roberta , Poloni Tino Emanuele , Medici Valentina , Colombo Mauro , Guaita Antonio
Published: December 2020

Background

Frailty is a frequent and potentially reversible age‐related syndrome. Current evidence supports the associations between Frailty, cognitive impairment and dementia. The aim of the study is to estimate the predictive role of Frailty syndrome in incident dementia and cognitive impairment, as well as the modulation of genetic‐psycho‐social factors, such as APOEɛ4 polymorphism and loneliness in a non‐demented Italian cohort of elderly individuals.

Method

Data are from a cohort of 1,321 persons aged 70‐74 years old, living in Abbiategrasso (Milan, Itay): the InveCe.Ab study (Guaita et al. 2013; clinical trials.gov NCT01345110). The sample took place in 2009 with follow‐ups in 2012 and 2014. Frailty was measured by Frailty Index (FI). The FI was then separated into Frail (FI>0.25), pre‐Frail (FI = 0.08‐0.25) and non‐Frail (FI < 0.08) groups. Dementia was defined using the DSM‐IV‐TR. Global cognition was assessed by the Mini Mental State Examination (MMSE), Comorbidity by Cumulative Illness Rating Scale (CIRS).

Result

Frailty was associated with cumulative incidence of dementia (p<0.001), MMSE score at baseline (p<0.001), difference in MMSE score between 2009 and 2014 (p 0.005), CIRS (p<0.001).After four follow‐up years, 4.6% developed Dementia. In the longitudinal regression models adjusted for age, gender, level of education and loneliness, APOEɛ4 carrier status, Frailty was associated with incident dementia (OR=7.75,95% CI 3.26‐18.41), with higher risk of dementia for frail men compared to women (OR=13.79, 95% CI 4.11–46.21; OR= 4.63, 95% CI 1.32‐16.26, respectively). In linear regression models, adjusted for the same variables, Frailty also showed a significant association with the decrease of MMSE score in follow‐up only in males (male: β ‐0.131,95% CI ‐7.16 – ‐0.15; females: β‐0.085, 95% CI ‐5.60 – 0.19). Other covariates, such as loneliness, were independently associated with the outcomes. However, the interaction term for loneliness and frailty was not significant in predicting incident dementia.

Conclusion

in our large population sample, Frailty is associated with cognitive impairment and cognitive decline. These results suggest that Frailty syndrome, especially if accompanied by other genetic‐psycho‐social characteristics such as loneliness, could be considered by clinicians as a red flag for early detection of cognitive disorders.
Research diagnostic criteria for Alzheimer’s disease: Findings from the multinational LipiDiDiet Trial
Authors: Rosenberg Anna , Solomon Alina , Soininen Hilkka , Visser Pieter Jelle , Blennow Kaj , Hartmann Tobias , Kivipelto Miia ,   LipiDiDiet Clinical Study Group
Published: December 2020

Background

LipiDiDiet is a randomized controlled trial investigating the effects of a multinutrient medical food product on change in cognition among individuals with prodromal AD. This study aimed at investigating participants’ baseline AD biomarker profile, including classification according to the IWG‐2 and NIA‐AA 2011 & 2018 diagnostic criteria, and assessing the impact on 2‐year cognitive/functional decline and progression to dementia.

Method

LipiDiDiet targeted 311 individuals aged 55–85 years at 11 sites in four countries. Prodromal AD was defined according to the IWG‐1 criteria: evidence for AD pathology (abnormality in any CSF or imaging biomarker) and episodic memory impairment. Key outcomes were e.g. change in cognition and function (Neuropsychological Test Battery NTB z‐scores, CDR‐SB) and progression to dementia. Linear mixed models were used to investigate change in NTB and CDR‐SB scores across different baseline biomarker profiles (biomarker profile x time interactions). Associations between biomarker profiles and risk of progression to dementia were analyzed with Cox proportional hazards models adjusted for randomization group, MMSE, and study site.

Result

CSF Aβ, t‐tau, and p‐tau levels were abnormal in 88%, 86%, and 69% of participants with centrally assessed CSF (N=107). 64% had an A+/T+/N+ profile. While cognitive/functional decline tended to be more pronounced in the IWG‐2 prodromal AD, NIA‐AA 2011 high and intermediate AD likelihood, and NIA‐AA 2018 AD groups, few statistically significant differences were observed between diagnostic groups within each set of criteria. Hazard ratio (95% CI) for progression to dementia was 4.7 (1.6–13.7) among participants with IWG‐2 prodromal AD (compared with no prodromal AD); 7.5 (1.0–55.0) for NIA‐AA 2011 high AD likelihood group (compared with SNAP), and 9.4 (1.2–72.7) for NIA‐AA 2018 AD group (compared with non‐Alzheimer’s pathologic change).

Conclusion

Despite being less restrictive than the more recent diagnostic criteria, IWG‐1 criteria reliably identified individuals with AD pathology. Findings may have implications for future trial design, as these criteria may be preferred due to feasibility in trials conducted in diverse settings, e.g. clinical trials which do not directly target Aβ or tau pathology.
Short‐ and long‐term effects of glycaemic load on cognition, dementia risk and plasma Amyloid‐β levels
Authors: Gentreau Mélissa , Chuy Virginie , Féart Catherine , Samieri Cécilia , Raymond Michel , Berticat Claire , Artero Sylvaine
Published: December 2020

Background

In animal models, carbohydrates increase β‐amyloid aggregation, tau phosphorylation and hippocampal atrophy which lead to the development of Alzheimer’s disease (AD). In epidemiological studies, cross‐sectional analyses on the impact of carbohydrate consumption on cognition are inconsistent. Besides, the long‐term effects of high carbohydrate intake on the risk of dementia and AD are poorly described. Here, we investigated i) the association between glycaemic load (GL) and cognition ii) the longitudinal association between GL and the onset of dementias (AD and others dementias) and iii) the associations between GL and plasma β‐amyloid peptides (Aβ) (possible biomarkers of AD pathology).

Method

No less than 2,777 non‐demented participants from the Three‐City Study (Bordeaux and Montpellier centre), aged over 65, filled a complete semi‐quantitative Food Frequency Questionnaire which was used to estimate GL (GL assesses both the carbohydrate quantity and quality, and reflects glycaemic response). At baseline, participants underwent a battery of neuropsychological tests (global cognition, visual memory, executive function, verbal fluency). Clinical diagnosis of dementia was made at each follow‐up (every 2‐3 years during 12 years). In a sub‐sample of 378 participants, plasma Aβ was measured. Plasma levels of Aβ1–40, Aβ1–42, Aβn‐40, and Aβn‐42 were measured using an xMAP‐based assay technology. We used Cox proportional hazards models to test the association between GL and the onset of dementia and linear regressions to test the associations between GL and cognitive performance or plasma Aβ.

Result

After adjustment for potential confounders (age, sex, education, APOE‐ε4, BMI, type 2 diabetes, hypertension, cardiovascular history, history of stroke, hypercholesterolemia, history of head trauma, good subjective health, tobacco, energy intake, Mediterranean diet, physical activity), high afternoon‐snack GL was associated with increased dementia risk in APOE‐ε4 carriers (HR = 1.27 [1.03‐1.56]). Unexpectedly, GL was associated with higher cognitive performance, particularly for global cognition and visual memory (p <.01). We found no significant association between GL and plasma Aβ.

Conclusion

High carbohydrate consumption was associated with a long‐term risk of dementia in APOE‐ε4 carriers. However, carbohydrate consumption seems to promote short‐term cognitive performance.
Bacteria isolated from the stools of Alzheimer’s disease patients exacerbate cognitive impairment in 3xTg AD mouse model
Authors: Marizzoni Moira , Tournier Benjamin , Pauis Arthur , Millet Philippe , Mirabelli Peppino , Salvatore Marco , Cattaneo Annamaria , Frisoni Giovanni B.
Published: December 2020

Background

Human microbiota‐associated (HMA) murine models are developed by gavaging mice with human bacteria or stools and are increasingly used to study the relation between the human microbiota and disease. The aim of this study is to evaluate the effect of gut bacteria isolated from donors with or without Alzheimer’s dementia on behavior in AD transgenic (Tg) mice.

Method

Sixty female, one‐year 3xTg mice (APPSWE, PS1M146V and TauP301L) received (1) antibiotic treatment (for 14 days before the first gavage), (2) stomach acid suppressant administration, (3) laxative administration (immediately before the first gavage) and, (4) microbiota transplantation (or saline, once every 2 weeks for 2 months). The transplanted microbiota consisted of bacteria isolated from stools of donors pertaining to four different profiles: i) amyloid positive AD patient, amyloid negative cognitively healthy subjects ii) with or iii) without protective APOE genotype and, iv) young healthy donor. As additional control, we included a group of mice that received bacteria isolated from stools of untreated 3xTg mice. Stools collection and behavioral assessment (open‐field test, Y‐maze test, radial maze test, elevated plus maze test) was performed before antibiotic treatment and at day 3, 30, 60 after the first gavage. All mice were sacrificed at day 60 for ex‐vivo assessments.

Result

After 60 days from the first gavage, the bacteria from the AD patient induced AD‐like behavior in 3xTg mice, including impaired general activity in the open‐field test and exacerbated anxiety in the elevated plus maze test, compared with mice that received saline or bacteria from untreated 3xTg mice. The bacteria from the other human donors did not influence mouse behavior.

Conclusion

The microbiota of AD patients induced an AD‐like phenotype in 3xTg mice. Brain and gut ex‐vivo assessments, 16S rRNA gene sequencing as well as behavioral longitudinal analysis are on‐going to evaluate the human microbiota transplantation efficiency and its effect on AD pathology and inflammation.
Identification of genomic biomarkers with machine learning for early and differential diagnosis of late‐onset Alzheimer’s disease (LOAD)
Authors: Erdoğan Onur , Esme Mert , Balci Cafer , Rafatov Sevda , Cankurtaran Mustafa , Yavuz Burcu Balam , İyigün Cem , Son Yeşim Aydın
Published: December 2020

Background

The complex genetic etiology of the LOAD is still unclear, which restrains the early and/or differential diagnosis of LOAD. Genome‐Wide Association Studies (GWAS) is designed to explore the statistical interactions of variants, but interactions between variants are overseen by the univariate analysis. The machine learning algorithms are able to capture hidden patterns for the understanding of complex genetic disorders.

Methods

The controlled accessed GWAS datasets provided by ADNI (210 controls and 344 cases), and GenADA (777 controls and 798 cases), and NCRAD (1310 controls and 1289 cases) initiatives. GWAS analysed with PLINK, following p‐value filtering for the initial dimension reduction. Random Forest (RF) implemented with 5‐fold cross‐validation (CV) using RANGER package in R. LOAD RF model variants mapped and consensus genes are selected.

Results

Test performances of LOAD‐RF models of ADNI, NCRAD and GenADA datasets were 72,9%, 68,8%, and 92,4% respectively. 390 variants from ADNI, 1740 from NCRAD, and 434 from GenADA datasets were included in the individual LOAD‐RF models.No consensus variants are observed, but when the genomic locations of the variants are mapped, 62 genes common to at least two datasets are identified. 5 out of 6 genes common in all three LOAD‐RF models were also found to be reported as differentially expressed in the AD vs control subclusters of astrocyte cells (LFC>0.5, FDR = 0.01) (Ref1). Enrichment analysis based on consensus genes revealed cell adhesion as the top GO term for biological processes.

Conclusion

The meta‐analysis of GWAS datasets for LOAD is performed, and the variants common in three predictive models at the gene level are analyzed. In the next phase of this study, the predictive performance of 6 variants are selected will be evaluated from the saliva samples collected from Turkish AD patients and controls. The outcomes of this study and know‐how acquired will allow us to offer an early/differential diagnostic tool based on the genotyping of the consensus variants for the early and differential diagnosis of the LOAD. Reference: (1) Grubman, A., et al. Nat Neurosci 22, 2087–2097 (2019).
Methylomic variation induced by LPS exposure in a microglial cell line
Authors: Imm Jennifer L.
Published: December 2020

Background

Despite extensive research, it is still unknown how AD pathogenesis occurs and how this links into the development of the pathological Aβ and Tau aggregates in the brain. More recent evidence has indicated that microglia may play a key role in AD risk and pathogenesis. This comes from large cohort studies identifying genetic variants associated with late onset Alzheimer’s disease with immune related functions. Chronic activation of microglia is thought to cause them to exist in a pre‐activated or “primed” state resulting in them having a heightened response to immune stimuli such as lipopolysaccharide. Despite increasing investigation into the role of microglia in Alzheimer’s disease onset and progression there are few studies focussed on the epigenomic consequences of chronic immune stimulation. However, in order to study this it is first important to understand the epigenomic consequences of acute immune stimulation.

Method

An immortalized primary microglial cell line (SV40; Accegen) were plated and underwent one of three treatments; 24 hour exposure to 1 µg/mL LPS, 24 hour exposure to 1 µg/mL LPS followed by a 24 hour recovery period, or no treatment (control). DNA was collected from cells and DNA methylation was assessed using the IlluminaEPIC array. Using median absolute derivation, linear modelling and pathway analysis we identified loci undergoing dynamic methylation changes upon LPS challenge and the cellular pathways these loci are associated with.

Result

This study has identified methylomic variation associated with microglial exposure to LPS and recovery. We identified 173 significant loci with these loci being associated with pathways such as extracellular matrix organisation, enzyme activity and organelle membranes. We have also shown there are no changes to epigenetic or mitotic age upon immune stimulation.

Conclusion

We have shown that there are epigenetic changes occurring upon acute microglial stimulation with LPS. These are changes occurring within pathways that are key to cellular function and response to response to infection. Finally we have shown that LPS exposure does not affect epigenetic or mitotic age. In the future it will be of interest to study DNA methylation changes in this microglia cell line after chronic exposure to LPS.
A novel proteomics assay allows parallel quantitation of a panel of synaptic proteins in human cerebrospinal fluid
Authors: Nilsson Johanna , Gobom Johan , Brinkmalm Gunnar , Zetterberg Henrik , Brinkmalm Ann , Blennow Kaj
Published: December 2020

Background

A reduction of synaptic activity is one of the earliest events in neurodegenerative diseases such as Alzheimer’s disease (AD)[1‐4]. A 35% loss in the number of synapses have also been found in AD, by using synaptic proteins as markers[3‐4]. Detection and quantification of synaptic markers is therefore a hot topic due to the significant role of synapses in the disease pathology and progression of neurodegenerative diseases. In this study, we developed a novel proteomics assay approach to quantify a panel of 17 synaptic proteins in cerebrospinal fluid. The synaptic panel includes but are not limited to: synucleins, neuronal pentraxins, SNARE proteins and neurogranin.

Method

Stable isotope labeled peptide standards were added during digestion of 100 µL CSF samples, followed by purification with solid‐phase extraction. Quantification was performed by micro‐high‐performance liquid chromatography (Ultimate 3000 standard liquid chromatography system, Thermo Fisher Scientific Inc,) parallel reaction monitoring mass spectrometry (Q Exactive, Thermo Fisher Scientific Inc.).

Result

We show a novel strategy to quantify 17 synaptic proteins in CSF in parallel to study several properties of synaptic pathology simultaneously. In a CSF pilot study of 20 AD and 20 healthy controls, several synaptic proteins were found to be increased (p‐value≤0.001) such as neurogranin, complexin‐2, VAMP2 and beta‐synuclein. Interestingly, the neuronal pentraxins (NPTX1, NPTX2 and NPTXR) showed no significant difference between AD and control.

Conclusion

We have successfully established a method that can measure and compare levels of a panel of synaptic proteins in individual patient CSF samples. The pilot study shows very promising results where several synaptic proteins potentially could be used as biomarkers for synaptic pathology in Alzheimer’s disease. References: (1) Bagetta, V., et al., Synaptic dysfunction in Parkinson's disease. Biochem Soc Trans, 2010. 38(2): p. 493‐7. (2) Schneider, J.A., et al., The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol, 2009. 66(2): p. 200‐8. (3) Schulz‐Schaeffer, W.J., The synaptic pathology of alpha‐synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol, 2010. 120(2): p. 131‐43. (4) Clare, R., et al., Synapse loss in dementias. J Neurosci Res, 2010. 88(10): p. 2083‐90.