bluuebunny/crossref_metadata_2025 huggingface dataset:
Late‐onset Alzheimer's disease‐associated gene, CPAMD8, increases B‐CTF and affects APP processing through regulation of the autophagy‐lysosome pathway
Authors: Qin Wei , Fernandez Victoria , Harari Oscar , Cruchaga Carlos , Benitez Bruno A.
Published: December 2020

Background

C3‐ and PZP‐like alpha‐2‐macroglobulin domain containing 8 (CPAMD8) has been shown to be associated with familial late‐onset Alzheimer disease (LOAD) in recent studies. However, the role of CPAMD8 in AD‐related phenotypes is currently unknown.

Methods

To determine whether CPAMD8 affects known AD‐related phenotypes, we used RNA‐sequencing data from AD patients and healthy controls from WUTSL and publicly available from the Mount Sinai Brain Bank (195 individuals). Differential expression (DE) analysis was performed using DESeq2 software. We investigated the association of CPAMD8 transcript levels with AD case–control status and CDR scores. CPAMD protein levels were quantified from AD cases and controls from the ADRC‐WUSTL cohorts (N=105). Mouse neuroblastoma (N2A) cells stably expressing wild‐type human APP695 (N2A‐APP) were transiently transfected with wild‐type (NM_015692) human CPAMD8 (RC213448, Origene). CPAMD8 mRNA and protein levels were confirmed by pPCR and western blot. The levels of Aβ40 and Aβ42 were measured in cell culture media by sandwich ELISA (Invitrogen).

Results

CPAMD8 is differential expressed in cases and controls and is associated with CDR score (p = 8.45×10‐3). Co‐expression gene network analysis place CPAMD8 in the amyloid pathway (p = 8.5×10‐5). A significant reduction in CPAMD8 protein levels was found in postmortem brain tissue from AD patients compared to controls (p = 2.1×10‐3). N2A‐APP cells expressing CPAMD8 exhibited a dose‐dependent reduction in extracellular Aβ40, Aβ42, sAPPα and sAPPβ levels, a decrease in full‐length APP, and a significant increase in intracellular levels of α and β APP C‐terminal fragments (CTF). No significant differences were detected in α‐secretase or γ‐secretase protein levels. However, inhibition of γ‐secretase induced much higher levels of LC3‐II, SQSTM1/p62 and APP CTFs, and lower levels of Aβ40 and Aβ42 in N2A‐APP cells expressing CPAMD8. A direct interaction between CPAMD8 and APP was confirmed by co‐immunoprecipitation. N2A‐APP cells, but not HEK293 cells, expressing CPAMD8 displayed a significant increase in LC3‐II and SQSTM1/p62. Pharmacological modulation of autophagy demonstrated an increased autophagic flux in N2A‐APP cells expressing CPAMD8.

Conclusions

Our data provides evidence that the AD‐associated gene, CPAMD8, alters APP processing through the regulation of the autophagy‐lysosome pathway.
Volumetry and cortical thickness of olfactory‐related structures in Alzheimer's disease: A systematic review and meta‐analysis
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin
Published: December 2020

Background

A lesser known early symptom of Alzheimer’s disease is the olfactory decline. The ability to identify an odour may even be a predictor of conversion from mild cognitive impairment (MCI) to AD. This sensory decline could reflect AD‐related brain damage, including cerebral atrophy of structures related to the sense of smell.

Method

The aim of this systematic review is to summarize current knowledge about the volume and cortical thickness of olfactory brain structures in the course of AD. Articles were collected from the PubMed database using the keywords olfac*, smell, MRI, volume, VBM, thickness, Alzheimer, MCI, POC, olfactory bulb, hippocamp*, amygdala, entorhinal cortex, piriform cortex. Articles were included in the review according to the following criteria: (1) participants had a diagnosis of AD or Mild Cognitive Impairment (MCI); (2) the presence of a healthy control group of the same age range; (3) cortical volume or thickness was calculated from MRI scans; and (4) there was an assessment of olfactory capacities. A meta‐analysis is in preparation.

Result

Twelve studies met the inclusion criteria. All of them report lower olfactory capacities in patients (AD or MCI). Eight studies report a reduced hippocampal volume and 9 studies relate olfactory capacities to hippocampal volume in these patients. Analogous results are found with the primary olfactory cortex. Amygdala and entorhinal cortex volumes are also affected, but their relationship to olfactory capacity is inconsistent. Only one study measured the volume of the olfactory bulb and reported no significant results. Links were also found between olfactory measurements and the volume of the pre‐central gyrus, ventricles and neocortex.

Conclusion

The olfactory decline observed in the early stages of AD may reflect brain damage already present in these stages, mainly to the hippocampus and the primary olfactory cortex. These findings support the proposition that an olfactory decline could be an early marker of AD.
Patient‐tailored, connectivity‐based forecasts of spreading brain atrophy in frontotemporal dementia
Authors: Brown Jesse , Seeley William W.
Published: December 2020

Background

Neurodegenerative diseases appear to progress by spreading via brain connections. Like Alzheimer’s disease, frontotemporal dementia (FTD) syndromes make compelling test cases for evaluating network‐based spreading models due to their focal and circumscribed atrophy patterns. In this talk, I will describe our recent work (Brown et al, 2019 Neuron) where we evaluated transneuronal degeneration by attempting to predict future atrophy in patients with behavioral variant frontotemporal dementia (bvFTD, n=42) and semantic variant primary progressive aphasia (svPPA, n=30). While evidence for this mode of progression has come from cross‐sectional studies, the critical test was whether network connectivity can predict longitudinal spread of atrophy in individual patients.

Methods

We used T1‐weighted MRI scans to identify each subject’s gray matter atrophy pattern. Using these maps, we identified each patient’s epicenter, the region whose healthy functional connectivity pattern most strongly resembled the patient’s atrophy. Next, we projected the patient’s epicenter and baseline atrophy map onto the healthy functional connectome. We used three measures to predict the amount future atrophy for 242 cortical and subcortical brain regions: 1) shortest path length to the epicenter (SPE); 2) nodal hazard, the amount of collective atrophy among a region’s first‐degree connected neighbors; and 3) regional baseline atrophy. A generalized additive model was used to generate predictions. Finally, we used a linear threshold model (LTM) to simulate disease spread from the identified epicenters.

Result

bvFTD patients had epicenters in anterior cingulate and frontoinsula and svPPA patients in the anterior temporal lobe. The predictive model explained an average of 37% within‐scan variance in longitudinal atrophy. SPE, nodal hazard, and baseline atrophy were all significant predictors of change (all p < 2x10‐16). The regions most vulnerable to subsequent atrophy were functionally connected to the epicenter and had intermediate levels of baseline atrophy. LTM simulations revealed that epicenter‐neighboring nodes were network hubs and may drive amplification of disease spread.

Conclusion

A statistical model using connectivity‐based predictors could accurately predict the whole‐brain subsequent atrophy patterns in most FTD patients. This provides new human evidence that neurodegenerative disease spreads between functionally connected areas. The findings represent a next step toward clinical application of the network‐based neurodegeneration framework.
Achieving supportive dementia‐friendly transportation: Research to practice implications
Authors: Silverstein Nina M
Published: December 2020

Background

Research has documented the impact of Alzheimer’s disease on critical driving skills (Adler, Rottunda, & Dysken, 2005; Eby et al., 2012). Impairments in driving are likely to be similar reasons that hinder use of public transit or other modes of travel. Figure 1 illustrates examples where the warning signs of AD not only present challenges to driving but also may affect the use of transportation options. Figure 2 illustrates the continuum from driver to passenger. A framework for perceiving mobility as the outcome and driving as just one mode of travel can succeed in reducing the perception of loss to the individual if models of supportive transportation are more available in practice.

Method

Drawing on the Dementia Friendly Calculator (Figure 3), and Silverstein and Turk (2015) interviews with transportation providers, supportive transportation is operationalized in terms of the level of assistance needed and whether transportation providers deliver that assistance. Understanding the 5As of availability, affordability, adaptability, accessibility, and acceptability led to strategies and tips for transportation providers, drivers, care partners, and the person with dementia.

Results

Strategies include pre‐trip checklists, passenger information; escorts to provide to the door, through the door, or stay at the destination assistance; training on communication and sensitivity in providing assistance in/out of vehicle.

Conclusion

Expanding the availability of supportive transportation options will enable persons with dementia to engage in their communities safely and longer throughout the disease process. References: Adler, G., Rottunda, S., & Dysken, M. (2005). The older driver with dementia: An updated literature review. Journal of Safety Research, 36(4), 399‐407. Eby, D., Silverstein, N., Molnar,L., LeBlanc,. D., Adler, G..(2012). Driving Behaviors in Early Stage Dementia: A Study Using In‐Vehicle Technology. Accident Analysis & Prevention. Kerschner, H.K., and Silverstein, N.M. (2018). Introduction to senior transportation. Routledge, New York. Silverstein, N.M., Dickerson, A., & Schold Davis, E. (2016). Community Mobility and Dementia: The Role for Health Care Professionals in Dementia Care: An Evidence‐Based Approach, Boltz, M., & Galvin, J., Editors. Springer Publications: 123‐148. Silverstein, N., & Turk, K. Students explore supportive transportation for older adults (2015). Gerontology & Geriatrics Education/Routledge Taylor & Francis.
Informal care time in dementia by cognitive, functional and behavioral disease severity from eight longitudinal cohorts across multiple countries
Authors: Handels Ron , Jönsson Linus , Green Colin , Winblad Bengt , Wimo Anders ,   Actifcare, ICTUS/DSA, IDA, LEARN, 4CD, MEDICIE, PLASA/DSA and RightTimePlaceCare Consortia Data Holder
Published: December 2020

Background

About half of the care for dementia is provided informally by family carers. Evidence on the hours of informal care by dementia symptoms of cognition, function and behavior is important to estimate the long‐term health‐economic effects beyond the common trial periods; especially as such evidence is not available from claims registries. We aim to estimate the informal care time provided by family carers to persons with dementia across states of cognition, function and behavior and demographic characteristics using merged data from multiple countries.

Method

Data was obtained from longitudinal cohorts Actifcare, ICTUS, IDA, LEARN, 4C, MEDICIE, PLASA and RightTimePlaceCare, including persons with Alzheimer’s and other type dementia recruited from a variety of clinical settings in countries BE, CH, DE, DK, EE, ES, FI, FR, GR, IE, IT, NL, NO, PT, SE and UK. Scores on cognition (MMSE), harmonized instrumental activities of daily living (IADLS, DAD) and neuropsychiatric symptoms (NPI) were categorized as mild, moderate or severe, resulting in 27 possible health states. Missing data were imputed using multiple imputation. Multivariate mixed regression models were fitted to the reported instrumental and personal informal care (obtained by the Resource Use in Dementia questionnaire) using the health states and demographic characteristics.

Result

A total of 10,310 observations from 4866 persons were available with mean baseline person with dementia age of 79 (SD=7.4) and 64% female, and mean informal carer age of 63 (SD=13.8), 66% female and 63% living together with the person with dementia. The mean hours of informal care per week are provided in figure 1. Regression indicated a positive association with cognition, function, behavior, home living, female and cohabiting informal carer (for both instrumental and personal informal care), and age had varying effects.

Conclusion

Informal care is associated to dementia disease severity across cognitive, functional and behavioral domains independently. The results can serve as input for country‐specific models for epidemiological projections and health‐economic simulation for the evaluation of (new) interventions from a societal perspective. The harmonized longitudinal dataset has the potential to estimate within‐individual changes in informal care related to disease progression over time.
Genetic studies of Alzheimer's disease risk implicate clearance of lipid rich debris in myeloid cells
Authors: Novikova Gloriia , T.C.W. Julia , Marcora Edoardo , Kapoor Manav , Renton Alan E. , Efthymiou Anastasia M. , Abud Edsel M. , Bendl Jaroslav M. , Cheng Haoxiang M. , Fullard John F. , Roussos Panos , Poon Wayne W. , Hao Ke , Goate Alison M.
Published: December 2020

Background

Genome‐wide association studies (GWAS) have identified more than forty loci associated with Alzheimer’s disease (AD), but the causal variants, regulatory elements and genes remain largely unknown, impeding a mechanistic understanding of AD pathogenesis. Earlier pathway analyses have implicated lipid metabolism, immune response and endocytosis.

Method

We used LDscore regression to determine the epigenomic annotations enriched for AD risk variants. We then integrated AD GWAS signals with epigenomic and transcriptomic datasets using novel analytical approaches to link myeloid enhancer activity to target gene expression regulation and AD risk modification.

Result

We show that AD risk variants are specifically enriched in active enhancers of monocytes, macrophages and microglia. Using summary‐data based Mendelian Randomization nominate candidate AD risk enhancers and identify their target causal genes (including AP4E1, AP4M1, APBB3, BIN1, CD2AP, MS4A4A, MS4A6A, PILRA, RABEP1, SPI1, SPPL2A, TP53INP1, ZKSCAN1, and ZYX) in sixteen loci. Fine‐mapping of these enhancers nominates candidate functional variants that likely modify disease susceptibility by regulating causal gene expression specifically in myeloid cells. In the APOE locus we used genome editing to generate isogenic human induced pluripotent stem cells (hiPSC) combined with transcriptomics to demonstrate dyshomeostasis of lipid metabolism in APOE44 glial cells from.

Conclusion

Combined, these results strongly implicate dysfunction of myeloid cell endo‐lysosomal pathways involved in clearance of lipid rich debris in the etiology of AD.
Gut microbiome perturbations influence brain amyloidosis only in the presence of microglia in APPPS1‐21 mice
Authors: Dodiya Hemraj B. , Lutz Holy , Weigle Ian , Roman‐Santiago Carlos , Patel Priyam , Olszewski Monica , Zhang Can , Zhang Xiaoqiong , Schipma Matthew John , Tanzi Rudolph E. , Gilbert Jack A. , Sisodia Sangram S.
Published: December 2020

Background

In prior efforts, we demonstrated reduced amyloidosis and altered microgliosis in long‐term antibiotics (abx)‐treated APPPS1‐21 male mice. Restoration of the gut microbiome into abx‐treated male mice by fecal microbiota transfer (FMT) established a causality between the gut microbiome and amyloidosis. We have used FMT studies using our current short‐term abx APPPS1‐21 mice to evaluate the microbiome‐microglia‐amyloidosis axis.

Method

Short‐term, postnatal abx (4mg/ml Kanamycin, 0.35mg/ml Gentamicin, 8500U/ml Colistin, 2.15mg/ml Metronidazole, 0.45mg/ml Vancomycin: post‐natal day 14 to day 21) was performed. To establish causality, we performed FMT (200µl of 5mg/ml fecal slurry daily gavage) into abx‐treated APPPS1‐21 male mice. Pathogenicity of the gut microbiome in WT or Tg mice were confirmed using age‐matched FMT from WT and Tg controls into abx‐treated male mice. We performed total RNAseq transcriptome analysis to evaluate potential mechanism(s). The role of microglial cells were evaluated in PLX6522 (CSF‐1 receptor inhibitor)‐treated FMT‐transplanted abx‐treated APPPS1‐21 male mice. Nine weeks old GF APPPS1‐21 were used to characterize the amyloidosis and glial cells in both genders.

Result

An early life abx treatment resulted in gut microbiota changes in a sex‐dependent manner. Only male mice showed reduced amyloidosis and altered microglial phenotypes. Age matched Tg FMT or WT FMT resulted in higher amyloidosis in abx‐treated male mice. RNAseq analysis of total cortical RNA showed significantly different mRNA levels that occurred in a sex‐specific manner and changes in abx‐treated male mice were restored with FMT. GO term analysis showed gliogenesis and microglia development as significantly altered pathways in abx‐treated male group only. To confirm the exact role of the microglia in this model, we employed PLX6522 in FMT‐treated ABX‐male mice. Microglia depletion did not result in an FMT‐dependent increase in amyloidosis in abx‐treated male mice. Finally, germ‐free APPPS1‐21 mice showed reduced amyloidosis that occurs in a sex‐specific manner.

Conclusion

From GF APPPS1‐21 and FMT‐treated abx‐male APPPS1‐21 studies, we conclude that gut microbiome plays a critical role in modulating amyloidosis in APPPS1‐21 mice. Furthermore, microglia mediates the effects of early life gut microbiota perturbations, which results in altered amyloidosis in APPPS1‐21 male mice.
Longer TOMM40 poly‐T variants associated with decreased regional gray matter in cognitively normal older APOE E3/E3 adults
Authors: Honea Robyn A , Vidoni Eric D , Morris Jill K , Michaelis Elias K , Burns Jeffrey M , Swerdlow Russell H
Published: December 2020

Background

The TOMM40 poly‐T is a polymorphism of the TOMM40 gene at rs10524523 (“523”), in linkage disequilibrium with APOE. The role of TOMM40 in Alzheimer’s disease risk is still controversial. We sought to use whole brain voxel‐based methods to investigate if older individuals with the absence of an APOE e4 allele with varying lengths of the TOMM40 Poly‐T allele had gray matter volume differences indicative of Alzheimer’s disease risk.

Method

We studied individuals without cognitive impairment (n=69) from our KU Alzheimer’s Disease Center whose apolipoprotein (APOE) genotype was e3/e3, and who were Caucasian. The participants were grouped according to poly‐T length polymorphisms at “523” homozygous for S (S/S; n=25), homozygous for VL (VL/VL; n=19), and heterozygous (S/VL; n=25). All individuals were scanned for T1‐weighted MPRAGE structural images using a 3T Skyra Siemens. Images were preprocessed and analyzed using CAT12, a Computational Anatomy Toolbox (http://www.neuro.uni‐jena.de/cat/) running under SPM12 and MATLAB (R2020a). To investigate associations between genotype and regional GM volume, we performed voxel‐based morphometry (VBM). In order to investigate associations between TOMM40 Poly‐T group and gray matter volume differences we included age, sex, and total intracranial volume (TIV), as variables of no interest in our full factorial model. The statistical threshold was set at Pheight < 0.05, corrected (FDR).

Result

All groups were similar and not significantly different in mean age, education, MMSE, and overall brain volume. Brain magnetic resonance scans were analyzed using the CAT12 program within SPM software. Individuals with a VL/VL genotype had lower precuneus volumes (p=.023 FDR corrected, k=213, ‐29, ‐84, 36) and temporal cortex volumes (p=.005 FDR corrected, k =362, ‐45, ‐40, ‐32) compared to S/S individuals.

Conclusion

TOMM40 “523” VL variants are related to reduced gray matter volume in the precuneus and temporal cortex in healthy individuals with an APOE e3/e3genotype. This is especially interesting as the precuneus has been identified in other studies, and it may be particularly sensitive to dysfunction in bioenergetic changes associated with faulty mitochondria. This adds to a growing literature implicating TOMM40 “523” and mitochondrial function in late‐onset Alzheimer’s disease progression.
Usefulness of the physical fitness test for screening cognitive impairment in the Korean elderly
Authors: Choi Muncheong , Chun Buong‐O , Moon So Young , Lee Sun Min , Sun Kyunghwa , Jeong Jee Hyang , Park Hee Kyung , Park Yoo Kyoung , Hong Chang Hyung , Na Hae Ri , Park Kyung‐Won , Kim Byeong‐Chae , Cho Soo Hyun , Choi Seong Hye , Song Hong‐Sun
Published: December 2020

Background

Physical performance as well as cognitive function decline as people are getting older. We aimed to evaluate usefulness of physical fitness measures for screening cognitive impairment in Korean elders.

Method

A total of 88 not‐demented individuals (Female: 80.0%, age: 70.6±5.1 yrs, Clinical Dementia Rating (CDR): 0(33%), 0.5(67%), Body Mass Index: 24.2±2.9 kg/m2)were recruited. Their physical fitness was assessed by grip power, sit‐to‐stand for 30 seconds, walking in place for 2 minutes, bending the upper body forward, standing on one foot while lifting the other knee up, 3m timed‐up‐and‐go (TUG), fast walking on an “8”‐ shaped trajectory (F8WT), T‐wall test and bioelectrical impedance analysis. In addition, their cognitive function was evaluated by Mini‐Mental State Examination (MMSE) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Correlation analysis was conducted to analyze the association between physical fitness and cognitive function. The receiver operating characteristic (ROC) analysis was applied to reveal diagnostic accuracy and optimal cutoff of each physical fitness test for cognitive impairment which was defined as CDR 0.5.

Result

In T‐wall test, time taken for 100 hits was negatively correlated with MMSE total score (r=‐0.497) and RBANS total score (r=‐0.532). The time taken for F8WT was significantly correlated with MMSE (r=‐0.405). F8WT, TUG, as well as T‐wall test showed large Area under the curve for defining cognitive impairment (TUG=.768, 95%CI= .650∼.885; F8WT=.735, 95%CI=.612∼.857; T‐wall=.682, 95%CI=.545∼.819). The optimal cut‐off to predict cognitive impairment was 6.0 sec in TUG (sensitivity=73.2%, specificity=73.1%), 26.3 sec in F8WT (sensitivity=71.4%, specificity=73.1%) and 94.5 sec in T‐wall test (sensitivity=62.5%, specificity=65.4%).

Conclusion

F8WT, TUG, as well as T‐wall test were found to be accurate and portable measures for screening cognitive impairment in Korean elders, and may be particularly useful for screening cognitive impairment in elderly populations with wide variation in educational levels.
A panel of blood lipids associated with cognitive performance, brain atrophy and diagnosis: A longitudinal study of elders without dementia
Authors: Ma Ya‐Hui , Yu Jin‐Tai , Tan Lan , Dong Qiang , Xu Wei , Tan Lin , Shen Xue‐Ning
Published: December 2020

Background

Blood metabolites have been suggested as promising biomarkers of Alzheimer’s disease. Identifying diagnostic and predictive lipids can provide new spots in worse cognitive decline fields.

Method

Total 579 plasma lipid signatures were sampled in 374 participants without dementia at baseline enrolled in the Alzheimer’s Disease Neuroimaging Initiative cohort over 10 years. Ten‐fold cross‐validated least absolute shrinkage and selection operator‐logistic regression selected a subset of lipids that best classified individuals with worse slopes of cognitive decline determined by linear mixed models. Multivariable adjusted model examined associations between lipids and neuropsychiatric assessments, CSF biomarkers, brain structural measures and diagnostic categories.

Result

In a training and a validation set, a panel of seventeen lipids classified cognitively declined individuals with favorable prediction (training set: area under curve [AUC]=0.768, 95% confidence interval [CI]=0.715‐0.821; validation set: AUC =0.747, 95%CI= 0.627‐0.867) and calibration efficacy (Hosmer‐Lemeshow test: p>0.05). Adding risk score to the predictive model yielded a better AUC of 0.779 (95%CI=0.712‐0.845) than the one with clinical variables alone (p=0.014). The model combining polygenic hazard score, lipid signature and clinical variables yielded the best improvement in prediction. Baseline lipid signatures consisting of all selected lipids independently predicted declined cognition and positively associated with baseline cognitive performance (p=0.007) and cerebrospinal tau protein changes (p‐tau, p=0.025; t‐tau, p=0.010). Longitudinal analyses showed lipid signatures had adverse impacts on cognitive performance and brain atrophy over 10 years, and predicted diverse diagnostic categories (case vs. control, stable mild cognitive impairment [MCI] vs. cognitively normal [CN], progressive MCI vs.CN, A+[positive β‐amyloid deposition] vs. A‐[negative β‐amyloid deposition] , A+T+ [positive tau pathology] vs. A‐T‐[negative tau pathology]) and a trend for progressive outcomes.

Conclusion

A comprehensive panel of peripheral lipids instead of individual lipid molecule could better diagnose and predict cognitive decline. Further, integrating genetic variations, proteins and other biological information in future may expand the fit of exited detect models.
Neuropsychiatric correlates of cerebral amyloid burden in a memory clinic sample
Authors: Kan Cheuk Ni , Zhang Liwen , Reilhac Anthonin , Hilal Saima , Gyanwali Bibek , Chen Christopher , Xu Xin
Published: December 2020

Background

Neuropsychiatric symptoms (NPS) affect quality of life for both patients and caregivers, worsen cognitive and functional impairment in elderly, and are associated with the development of dementia. Manifestations of neurodegenerative and vascular pathologies including abnormal amyloid deposition and cerebrovascular disease (CeVD) often co‐exist in both cognitively normal and impaired elderly. However, the impact of co‐occurrence of amyloid and CeVD on major clinical outcomes, such as neurocognition and neuropsychiatric disorders, have not been extensively explored. Hence, the present study aimed to determine the neuropsychiatric correlates of cerebral amyloid burden amongst patients across a spectrum of cognitive impairment, adjusting for significant CeVD. We hypothesized that amyloid burden is independently associated with NPS severity.

Method

Participants with or without cognitive impairment from the memory clinic underwent [11C]PiB‐PET and MRI scans between April 2016 and September 2018. NPS were assessed using the 12‐item neuropsychiatric inventory. CeVD markers (cortical infarcts, stenosis, white matter hyperintensities, lacunes, and microbleeds) were graded and significant CeVD was defined following previously validated criteria. The association of NPS severity with global standardized uptake value ratio (SUVR) was analyzed using generalized linear models, controlling for demographics, diagnosis, cognitive function, depression status, and significant CeVD. Possible interactions between amyloid and CeVD were evaluated. The correlations between NPS subsyndromes and regional amyloid uptake were also explored. Holm‐Bonferroni correction was applied to adjust for multiple comparisons.

Results

Data for 168 participants [age=75.6 (7.3); female=93 (55.4%); MMSE=22.3 (5.7)] were analyzed, including 24 cognitively normal, 89 MCI, and 55 with dementia. Global SUVR was associated with higher total NPS score [β (CI)=0.67 (0.15‐1.18), p=0.011], driven by hyperactivity subsyndrome [β (CI)=0.96 (0.15‐1.11), p=0.002] and apathy subsyndrome [β (CI)=0.90 (0.34‐1.45), p=0.002]. Apathy subsyndrome was positively correlated with amyloid uptake in the thalamus (r=0.25, p=0.002) and parietal region (r=0.224, p=0.002). There was no significant interaction between global SUVR and significant CeVD on NPS.

Conclusion

Neuropsychiatric manifestations reflect underlying neurodegenerative pathology independent of vascular burden, suggesting that amyloid and CeVD may exert their effects through different pathways. This finding contributes to the neuropathological understanding of neuropsychiatric disorders, thus informs future development of novel treatment and monitoring of disease progression.
Characteristics of behavioral and psychological symptoms of dementia in long‐term care facility residents: An item response theory approach
Authors: Arai Asuna , Katsumata Yuriko , Ozaki Takashi , Khaltar Amartuvshin
Published: December 2020

Background

Behavioral and psychological symptoms of dementia (BPSD) are a well‐known risk factor for an increased burden of care for staff in long‐term care facilities and family caregivers. The factors that contribute to BPSD development are multifaceted, and it is difficult to establish universal solutions for the different types of BPSD in different individuals. This study investigated the characteristics of each symptom and people with dementia using latent trait of BPSD appearance by item response theory.

Method

We conducted a cross‐sectional survey of older residents with dementia in 2015 at 10 selected long‐term care facilities in Hokkaido, Japan. Data were collected with a questionnaire completed by care staff. The questionnaire included a brief questionnaire form of the Neuropsychiatric Inventory (NPI‐Q), a standardized scale to assess 12‐item BPSD. Of the participants (n=312), we excluded 11 who had severe disability in daily living or were almost bed‐ridden and 104 for whom no medical records on cause of dementia were available. The two‐parameter logistic model was used to estimate an item difficulty and item discrimination for each symptom. We examined the association between the person parameters, latent BPSD score, and sociodemographic characteristics of the participants using Welch’s t test or ANOVA.

Result

Of the 197 residents with dementia (women: 81.7%, mean age: 86.4±7.7 years), agitation was the most prevalent symptom in BPSD, followed by irritability and apathy. The difficulty of symptoms was lower in agitation, irritability, aberrant motor behaviors, and disinhibition. This means that those having even lower latent BPSD scores could appear these symptoms. Conversely, hallucinations, euphoria, anxiety, and delusions, which showed higher difficulty, could be exhibited in those with higher latent BPSD scores. Apathy, night‐time disturbances, depression, and appetite disturbances showed too high difficulty and too low discrimination. The latent BPSD scores were not associated with sex, age, place of residence, cause of dementia, but with ADL and cognitive functions.

Conclusion

We demonstrated that some of BPSD symptoms could be characterized by latent trait on BPSD appearance. The characteristics based on latent BPSD trait might be useful to consider the measures of addressing BPSD.
Acute phase markers in CSF reveal inflammatory changes in Alzheimer’s disease that are impacted by APOE ε4, sex and age but not pathology
Authors: Ayton Scott , Janelidze Shorena , Roberts Blaine R. , Palmqvist Sebastian , Kalinowski Pawel , Diouf Ibrahima , Belaidi Abdel Ali , Stomrud Erik , Bush Ashley I , Hansson Oskar
Published: December 2020

Background

Neuroinflammation may accelerate Alzheimer’s disease (AD) progression. We profiled acute phase response (APR) proteins (stimulated by IL‐6 released from pro‐inflammatory glia) in CSF of people along the clinical and pathology (CSF t‐tau/Aβ42) spectrum of AD to investigate the association between disease outcomes and inflammatory changes.

Methods

APR proteins in CSF from 920 subjects in the Swedish BioFINDER study were quantitively analyzed using multiple reaction modelling mass spectrometry: α1‐antitrypsin, α1‐antichymotrypsin, ceruloplasmin, complement C3, α‐fibrinogen, β‐fibrinogen, γ‐fibrinogen, haptoglobin, and hemopexin. Ferritin was measured using multiplex ELISA. CSF t‐tau and Aβ42 was measured using Euroimmun ELISA and the cohort was dichotomized for AD pathology using the t‐tau/Aβ42 ratio. Subjects were also stratified by the following clinical diagnoses: cognitively normal (CN); subjective cognitive decline (SCD); mild cognitive impairment (MCI); and AD dementia. N per group was: CN t‐tau/Aβ42‐ve=335; CN t‐tau/Aβ42+ve=104; SCD t‐tau/Aβ42‐ve=105; CN t‐tau/Aβ42+ve=44; MCI t‐tau/Aβ42‐ve=78; MCI t‐tau/Aβ42+ve=133; AD t‐tau/Aβ42+ve=121.

Results

In separate multiple regressions (adjusting for diagnosis, age, sex, APOE‐ε4), CSF t‐tau/Aβ42 status did not affect APR protein levels in CN and SCD subjects (Figure 1). Rather, the APR elevated with symptomatic progression: MCI t‐tau/Aβ42+ve subjects had 4/10 proteins elevated compared to CN tau/Aβ42‐ve subjects (α1 antichymotrypsin, ferritin, α‐fibrinogen, β‐fibrinogen; 0.001<P<0.027), and all 10 proteins were elevated in AD (1.6x10‐8<P<0.017). Surprisingly, the APR was more robustly activated in people with cognitive changes but with low t‐tau/Aβ42 levels (7/10 and 5/10 proteins elevated in SCD and MCI respectively). APOE ε4 status did not affect levels of any APR proteins in CSF, while these were elevated in females and with increased age. The performance of the APR in predicting clinical diagnosis was greater in females, in younger subjects, and those without APOE ε4 (Figure 2).

Conclusions

The APR in CSF reveals inflammatory changes that occur with clinical and not pathological dimensions of AD. The APR has a complex interaction with clinical variables: the extent of the APR is affected by sex and age, not APOE ε4, yet the APR has more influence in non‐ε4 carriers, younger people and females (Figure 3). These data provide new insight into neuroinflammation in AD and how this varies according to demographics.
Lipid peroxidation status in cerebrospinal fluid samples from Alzheimer disease
Authors: Peña‐Bautista Carmen , Álvarez Lourdes , Baquero Miguel , López‐Nogueroles Marina , Hervás‐Marín David , Cháfer‐Pericás Consuelo
Published: December 2020

Background

Oxidative stress has been postulated as one of the mechanisms implied in Alzheimer Disease (AD). Brain lipids are especially vulnerable against reactive species due to the high metabolic activity in the brain. Our previous studies reported the utility of lipid peroxidation biomarkers in plasma as potential AD diagnosis biomarkers. The aim of this work is to study the brain specificity for these biomarkers.

Method

Lipid peroxidation products (isoprostanes, isofurans, neuroprostanes, neurofurans) were determined in cerebrospinal fluid (CSF) and plasma samples from AD patients (n= 42) and non‐AD participants (n= 34). For this, an analytical method based on liquid chromatography coupled to mass spectrometry was used. Participants’ classification was carried out following the NIA‐AA criteria based on standard CSF biomarkers, structural neuroimaging and neuropsychological evaluation. Correlations between both biofluids were evaluated by means of Pearson Correlation.

Result

Most of the determined analytes did not show correlation between plasma and CSF levels. Only the compound 17(RS)‐10‐epi‐SC‐Δ15‐11‐dihomo‐IsoF showed a slight correlation between both matrices. However, CSF lipid peroxidation levels showed correlation with CSF amyloid beta or tau levels.

Conclusion

CSF lipid peroxidation biomarkers levels could reflect amyloid pathology and cognitive impairment associated to AD. However, these levels are not directly correlated with the corresponding plasma concentrations, probably due to transport alterations through the blood brain barrier.
Association of odor identification capacity with amyloid‐β and tau burden in older adults: A systematic review and meta‐analysis
Authors: Tu Lihui , Lv Xiaozhen , Fan Zili , Zhang Ming , Yu Xin , Wang Huali
Published: December 2020

Background

Previous studies have shown that smell identification test might predict cognitive decline in older adults. However, whether the odor identification capacity correlates to the pathological change of Alzheimer’s disease (AD) has not been fully investigated. The systematic review aimed to examine the association between odor identification capacity and the amyloid‐β (Aβ) and tau burden in older adults.

Method

Electronic databases (MEDLINE, PsycINFO, Google Scholar) were searched up to June 2019 to identify studies that reported the correlation coefficients or regression coefficients between odor identification test scores and Aβ or tau levels in cerebrospinal fluid (CSF) or Aβ burden detected by 11C‐Pittsburgh compound B (PiB) positron emission tomography (PET). The protocol was pre‐specified (PROSPERO CRD42019138642).

Result

660 abstracts were retrieved, and 30 full‐text articles further explored, from which 24 were excluded. In the final sample, we identified four studies (468 participants) regarding Aβ PiB PET and two studies (223 participants) about Aβ or tau levels in CSF. There was a significant inverse linear relationship between odor identification test scores and global PiB binding (pooled correlation coefficient = ‐0.35, 95% confidence interval (CI)= ‐0.54∼‐0.13, p=0.002). There was no significant association between CSF Aβ1‐42 levels and odor identification test score (pooled correlation coefficient = 0.22, 95% CI= ‐0.04∼0.45, p=0.097). Due to lack of data, no pooled correlation coefficients could be computed on the association between odor identification test score and CSF tau level or the ratio of the Aβ1‐42 and tau.

Conclusion

There was an inverse association between odor identification capacity and global cerebral Aβ burden in older adults. It suggests that odor identification capacity might be a proxy marker of preclinical Alzheimer’s disease.
Functional interpretation of genetic risk loci for dementia using a protein quantitative trait loci (pQTLs) approach in cerebrospinal fluid
Authors: Reus Lianne M. , Jansen Iris E. , Tijms Betty M. , Visser Pieter Jelle , Lemstra Afina W. , Pijnenburg Yolande A.L. , van Der Flier Wiesje , Teunissen Charlotte E. , Campo Marta Del
Published: December 2020

Background

Genome‐wide association studies have successfully identified genetic risk loci for dementia,but through which biological mechanisms these factors contribute to dementia remains elusive. Cerebrospinal fluid (CSF) protein levels reflect ongoing biological processes that take place in the brain. Studying which CSF proteins associate with dementia risk loci could reveal intermediate molecular pathways connecting genetic variance to the development of disease.We aimed to identify protein quantitative trait loci (pQTLs) in ante‐mortem CSF in different types of dementia, including Alzheimer’s disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD).

Method

We included 513 subjects (144 non‐demented controls, 211 AD, 56 DLB, 102 FTD, age 64 ± 9 years, 36%female) from the Amsterdam Dementia Cohort and European Medical Information Framework for AD (EMIF‐AD) PreclinAD cohort who had genetic and CSF proteomic data available. Genetic data was generated using the Illumina Genome Screening Array(GSA). CSF proteins (n = 665) were measured using an antibody‐based proteomic array (Olink). We included 43 genetic risk loci for AD, 7 for DLB and 9 for FTD. Association signals between SNPs and CSF protein levels were determined using linear regression, adjusted for principal components, age and sex, stratified for diagnosis (i.e., non‐demented controls and diagnostic group combined). Results were corrected for multiple comparisons with the Bonferroni method.

Result

Variants in three AD (CR1, ZCWPW1, HESX1) and one DLB (GBA) risk loci were associated with levels of seven CSF proteins (Figure 1). The CR1 risk locus (rs4844610) was associated with higher CR2 CSF levels (P = 5.47 × 10−7), ZCWPW1 (rs2906657) with lower PILRB (P = 2.28 × 10−32) and HESX1 (rs186108507) with higher RETN (P = 6.00 × 10−8). Within DLB, GBA (rs12742181) was associated with higher CSF protein levels of ANG, CD798, CXCL13 and TNFRS13B (P = 7.79 × 10−7, P = 8.83 × 10−8, P = 4.87 × 10−6, P = 4.47 × 10−8 respectively). No significant associations were identified between FTD risk loci and CSF protein levels.

Conclusion

We identified four pQTLs in ante‐mortem CSF, providing a neurobiological link by which genetic risk loci potentially contribute to the development of AD and DLB. Dissecting the contribution of risk loci to neurobiological processes aids in understanding the complex disease mechanisms underlying different types of dementia. Our efforts are currently being extended to functional validation and genetic replication in independent cohorts.
Associations between ophthalmic conditions and risk of dementia in older adults
Authors: Hwang Phillip H , Longstreth WT , Thielke Stephen , Francis Courtney E , Carone Marco , Fitzpatrick Annette L
Published: December 2020

Background

It remains unclear whether common ophthalmic conditions in older adults, such as age‐related macular degeneration (AMD), diabetic retinopathy (DR), glaucoma, and cataracts, are related to dementia by causing vision loss or serving as markers of underlying neurodegenerative processes, such as Alzheimer’s disease (AD). We examined associations between these ophthalmic conditions and risk of dementia, including AD and vascular dementia (VaD).

Method

We identified 3,236 participants without dementia from the Cardiovascular Health Study (CHS) Cognition Study who were aged ≥65 years and underwent cranial MRI. Presence of AMD, DR, glaucoma, and cataracts were based on ICD‐9 and CPT codes from Medicare Part B and CHS medical records. Dementia classification was completed by consensus committee using data from neuropsychiatric tests or by other data for deceased participants or those unable to come into the clinic. Cranial MRIs were used for classification of dementia subtype. AD was determined using the National Institute of Neurological and Communication Disorders and Stroke – Alzheimer’s Disease and Related Disorders Association criteria. VaD was determined using the Alzheimer’s Disease Diagnostic and Treatment Centers criteria. Cox models with time‐varying exposure and adjustment for demographics, health behaviors and conditions, and ApoE genotype were used to evaluate associations between these four ophthalmic conditions and risk of all‐cause dementia, AD, and VaD.

Result

Increased risk of all‐cause dementia and VaD was significantly associated with AMD, DR, and cataracts, while increased risk of AD was significantly associated with AMD and cataracts (Table 1). When accounting for treatment status, glaucoma was significantly associated with increased risk of all‐cause dementia (HR: 1.53; 95% CI: 1.09 – 2.16; p = 0.015), but all other results remained similar. ApoE genotype was a significant effect modifier as only those without an ɛ4 allele were at increased risk for dementia associated with DR (HR: 5.14; 95% CI: 2.63 – 10.05; p<0.0001) and glaucoma (HR: 1.64; 95% CI: 1.13 – 2.39; p = 0.01).

Conclusion

AMD, DR, glaucoma, and cataracts were associated with increased risk of dementia, though not all by the same pathways as some were more strongly related to AD, while others were more strongly related to VaD.
Distinct relationships of self‐reported subjective memory decline to neurodegeneration across the Alzheimer's clinical continuum
Authors: Kuhn Elizabeth , Perrotin Audrey , Tomadesso Clémence , Andre Claire , Sherif Siya , Bejanin Alexandre , Touron Edelweiss , Landeau Brigitte , Mézenge Florence , La Sayette Vincent De , Vivien Denis , Chetelat Gael
Published: December 2020

Background

Self‐reported memory decline (SMD) is associated with increased risk of cognitive decline and neurodegeneration in patients with no or mild cognitive deficits, while diverging findings are reported in later clinical stages of the Alzheimer’s clinical continuum. Our aim is to provide a comprehensive overview of the relationships of SMD to brain volume and glucose metabolism across the entire cognitive spectrum, from normal cognition to dementia.

Method

We used data from two independent cohorts, including 180 participants from IMAP+ (64 controls, 30 subjective cognitive decline (SCD), 50 mild cognitive impairment (MCI) and 36 AD‐dementia patients) and 731 participants from ADNI (147 controls, 84 SCD, 369 MCI and 121 AD‐dementia). We assessed the voxelwise links between SMD and neuroimaging measures of atrophy (T1‐MRI GM volume) and hypometabolism (partial volume effect (PVE)‐corrected FDG‐PET data) within each cohort, and tested for an interactive effect of clinical stage or global cognitive impairment, to assess whether these links differed across cognitive/clinical stages. All analyses were adjusted for age, gender and education (p<0.005, cluster‐level corrected for multiple comparisons).

Results

We found only negative interactive effects of the cognitive/clinical stage, such that SMD and neuroimaging measures were negatively associated (more neurodegeneration with higher SMD) in early stages, while they were positively associated (more neurodegeneration with lower SMD) in late stages. This effect was particularly clear‐cut and similar in both cohorts for glucose metabolism and when splitting participants by cognitive stages (tercile of MMSE score; Figure 1), rather than by clinical groups (Figure 2), likely as the sampling of SCD and MCI patients differ between cohorts. Findings were recovered when using an episodic memory score instead of the MMSE to grade cognitive deficits’ severity, using PVE‐uncorrected FDG‐PET data, and restricting the analyses to the amyloid‐positive participants.

Conclusion

Our findings reveal a reverse relationship of SMD to neurodegeneration, indicating that SMD should be interpreted differently in early versus late stages of the Alzheimer’s clinical continuum. At early (e.g. SCD) stage, greater SMD is indicative of greater neurodegeneration, while at later stages (late MCI or dementia), lower SMD is indicative of greater neurodegeneration, probably as a reflect of anosognosia.