Journal of Alzheimer's Disease - Volume 79, issue 1

Authors: Zeng, Qingze | Li, Kaicheng | Luo, Xiao | Wang, Shuyue | Xu, Xiaopei | Li, Zheyu | Zhang, Tianyi | Liu, Xiaocao | Fu, Yanv | Xu, Xiaojun | Wang, Chao | Wang, Tao | Zhou, Jiong | Liu, Zhirong | Chen, Yanxing | Huang, Peiyu | Zhang, Minming | and for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Predicting the prognosis of mild cognitive impairment (MCI) has outstanding clinical value, and the hippocampal volume is a reliable imaging biomarker of AD diagnosis. Objective: We aimed to longitudinally assess hippocampal sub-regional difference (volume and asymmetry) among progressive MCI (pMCI), stable MCI (sMCI) patients, and normal elderly. Methods: We identified 29 pMCI, 52 sMCI, and 102 normal controls (NC) from the ADNI database. All participants underwent neuropsychological assessment and 3T MRI scans three times. The time interval between consecutive MRI sessions was about 1 year. Volumes of hippocampal subfield were measured by Freesurfer. Based on the …analysis of variance, repeated measures analyses, and receiver operating characteristic curves, we compared cross-sectional and longitudinal alteration sub-regional volume and asymmetry index. Results: Compared to NC, both MCI groups showed significant atrophy in all subfields. At baseline, pMCI have a smaller volume than sMCI in the bilateral subiculum, molecular layer (ML), the molecular and granule cell layers of the dentate gyrus, cornu ammonis 4, and right tail. Furthermore, repeated measures analyses revealed that pMCI patients showed a faster volume loss than sMCI in bilateral subiculum and ML. After controlling for age, gender, and education, most results remained unchanged. However, none of the hippocampal sub-regional volumes performed better than the whole hippocampus in ROC analyses, and no asymmetric difference between pMCI and sMCI was found. Conclusion: The faster volume loss in subiculum and ML suggest a higher risk of disease progression in MCI patients. The hippocampal asymmetry may have smaller value in predicting the MCI prognosis. Show more

Keywords: Alzheimer’s disease, hippocampal subfields, mild cognitive impairment, molecular layer, subiculum

DOI: 10.3233/JAD-200775

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 237-247, 2021

Authors: Bastrup, Joakim | Hansen, Kathrine H. | Poulsen, Thomas B.G. | Kastaniegaard, Kenneth | Asuni, Ayodeji A. | Christensen, Søren | Belling, Dorthe | Helboe, Lone | Stensballe, Allan | Volbracht, Christiane

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition of senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently. Objective: To characterize the proteomic profile of SPs and surrounding tissue in a mouse model of AD in 10-month-old tgAPPPS1-21 mice after chronic treatment with aducanumab for four months with weekly dosing (10 mg/kg). Methods: After observing significant reduction of SP numbers in hippocampi of aducanumab-treated mice, we applied a localized proteomic analysis by combining laser microdissection and liquid chromatography-tandem mass spectrometry (LC-MS/MS) of the remaining SPs …in hippocampi. We microdissected three subregions, containing SPs, SP penumbra level 1, and an additional penumbra level 2 to follow the proteomic profile as gradient. Results: In the aducanumab-treated mice, we identified 17 significantly regulated proteins that were associated with 1) mitochondria and metabolism (ACAT2, ATP5J, ETFA, EXOG, HK1, NDUFA4, NDUFS7, PLCB1, PPP2R4), 2) cytoskeleton and axons (ADD1, CAPZB, DPYSL3, MAG), 3) stress response (HIST1H1C/HIST1H1D, HSPA12A), and 4) AβPP trafficking/processing (CD81, GDI2). These pathways and some of the identified proteins are implicated in AD pathogenesis. Proteins associated with mitochondria and metabolism were mainly upregulated while proteins associated with AβPP trafficking/processing and stress response pathways were mainly downregulated, suggesting that aducanumab could lead to a beneficial proteomic profile around SPs in tgAPPPS1-21 mice. Conclusion: We identified novel proteomic patterns of SPs and surrounding tissue indicating that chronic treatment with aducanumab could inhibit Aβ toxicity and increase phagocytosis and cell viability. Show more

Keywords: Alzheimer’s disease, amyloid, mass spectrometry, therapeutics

DOI: 10.3233/JAD-200715

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 249-265, 2021

Authors: Couch, Elyse | Mueller, Christoph | Perera, Gayan | Lawrence, Vanessa | Prina, Matthew

Article Type: Research Article

Abstract: Background: Dementia policy states that the early diagnosis of dementia can keep people living well for longer; however, there is little robust evidence to support this. Mild cognitive impairment (MCI) is considered a prodrome to dementia and can aid with the earlier diagnosis of dementia. Objective: The objective of this study was to use a previous diagnosis of MCI, before dementia, as a proxy for early diagnosis to investigate the relationship between an early diagnosis and mortality. Methods: A retrospective cohort study of electronic health care records from South London and Maudsley NHS. Patients aged 50+, …diagnosed with dementia between January 2008 and November 2018, were divided into two groups: those with a previous diagnosis of MCI (early diagnosis) and those without. Cox regression models used to compare the risk of mortality between groups. Results: Of 18,557 participants, 5.6%(n  = 1,030) had an early diagnosis; they had fewer cognitive, psychiatric, and functional problems at dementia diagnosis. The early diagnosis group had a reduced hazard of mortality (HR = 0.86, CI = 0.77–0.97). However, the magnitude of this effect depended on the scale used to adjust for cognitive difficulties. Conclusion: A previous diagnosis of MCI is a helpful proxy for early diagnosis. There is some evidence that an early diagnosis is associated with a reduced risk of mortality; however, it is not clear how Mini-Mental State Exam scores affect this relationship. While these findings are promising, we cannot be conclusive on the relationship between an early diagnosis and mortality. Show more

Keywords: Alzheimer’s disease, dementia, early diagnosis, mild cognitive impairment, mortality

DOI: 10.3233/JAD-200978

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 267-274, 2021

Authors: Sergott, Robert C. | Raji, Annaswamy | Kost, James | Sur, Cyrille | Jackson, Saheeda | Locco, Amy | Patel, Arpankumar | Furtek, Christine | Mattson, Britta | Egan, Michael F.

Article Type: Research Article

Abstract: Background: We performed exploratory analyses of retinal thickness data from a clinical trial of the AβPP cleaving enzyme (BACE) inhibitor verubecestat in patients with Alzheimer’s disease (AD). Objective: To evaluate: 1) possible retinal thickness changes following BACE inhibition; and 2) possible association between retinal thickness and brain atrophy. Methods: Retinal thickness was measured using spectral-domain optical coherence tomography in a 78-week randomized placebo-controlled trial of verubecestat in 1,785 patients with mild-to-moderate AD. Changes from baseline in retinal pigment epithelium, macular grid retinal nerve fiber layer, central subfield retinal thickness, and macular grid volume were evaluated for …verubecestat versus placebo. Correlation analyses were performed to investigate the potential association between macular grid retinal nerve fiber layer and central subfield retinal thickness with brain volumetric magnetic resonance imaging (vMRI) data at baseline, as well as correlations for changes from baseline at Week 78 in patients receiving placebo. Results: Verubecestat did not significantly alter retinal thickness during the trial compared with placebo. At baseline, mean macular grid retinal nerve fiber layer and central subfield retinal thickness were weakly but significantly correlated (Pearson’s r values≤0.23, p -values < 0.01) with vMRI of several brain regions including whole brain, hippocampus, and thalamus. At Week 78, correlations between retinal thickness and brain vMRI changes from baseline in the placebo group were small and mostly not statistically significant. Conclusion: BACE inhibition by verubecestat was not associated with adverse effects on retinal thickness in patients with mild-to-moderate AD. Correlations between retinal thickness and brain volume were observed at baseline. Trial registration: Clinicaltrials.gov NCT01739348 (registered December 3, 2012; https://clinicaltrials.gov/ct2/show/NCT01739348 ). Show more

Keywords: Alzheimer’s disease, BACE inhibitor, brain atrophy, EPOCH, randomized clinical trial, retinal thickness, spectral-domain optical coherence tomography, verubecestat, volumetric magnetic resonance imaging

DOI: 10.3233/JAD-200735

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 275-287, 2021

Authors: Taudorf, Lærke | Nørgaard, Ane | Waldemar, Gunhild | Laursen, Thomas Munk

Article Type: Research Article

Abstract: Background: It remains unclear whether the increased focus on improving healthcare and providing appropriate care for people with dementia has affected mortality. Objective: To assess survival and to conduct a time trend analysis of annual mortality rate ratios (MRR) of dementia based on healthcare data from an entire national population. Methods: We assessed survival and annual MRR in all residents of Denmark ≥65 years from 1996–2015 using longitudinal registry data on dementia status and demographics. For comparison, mortality and survival were calculated for acute ischemic heart disease (IHD) and cancer. Results: The population comprised …1,999,366 people (17,541,315 person years). There were 165,716 people (529,629 person years) registered with dementia, 131,321 of whom died. From 1996–2015, the age-adjusted MRR for dementia declined (women: 2.76 to 2.05; men: 3.10 to 1.99) at a similar rate to elderly people without dementia. The sex-, age-, and calendar-year-adjusted MRR was 2.91 (95%CI: 2.90–2.93) for people with dementia. MRR declined significantly more for acute IHD and cancer. In people with dementia, the five-year survival for most age-groups was at a similar level or lower as that for acute IHD and cancer. Conclusion: Although mortality rates declined over the 20-year period, MRR stayed higher for people with dementia, while the MRR gap, compared with elderly people without dementia, remained unchanged. For the comparison, during the same period, the MRR gap narrowed between people with and without acute IHD and cancer. Consequently, initiatives for improving health and decreasing mortality in dementia are still highly relevant. Show more

Keywords: Dementia, mortality, nationwide study, survival, time trend

DOI: 10.3233/JAD-200823

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 289-300, 2021

Authors: Sun, Lin | Li, Wei | Yue, Ling | Xiao, Shifu

Article Type: Research Article

Abstract: Background: TAR DNA-binding protein-43 (TDP-43) and neurofilament light chain (NfL) are promising fluid biomarkers of disease progression for various dementia. Objective: We would explore whether blood levels of NfL and TDP-43 could predict the long-term progression to dementia, and the relationship of TDP-43 levels between cerebrospinal fluid (CSF) and blood. Methods: A total of 86 non-dementia elderly received 7-year follow-up, and were divided into 49 stable normal control (NC)/mild cognitive impairment (MCI) subjects, 19 subjects progressing from NC to MCI, and 18 subjects progressing from NC/MCI to dementia. Blood TDP-43 and NfL levels, and cognitive functions …were measured in all subjects. Furthermore, another cohort of 23 dementia patients, including 13 AD and 10 non-AD patients received blood and CSF measurements of TDP-43. Results: In cohort 1, compared to stable NC/MCI group, there were higher levels of blood TDP-43 at baseline in subjects progressing from NC/MCI to dementia. The combination of baseline blood TDP-43 levels with demographics including age, education, and diabetes had the detection for dementia occurrence. Baseline blood levels of NfL are negatively associated with cognitive function at 7-year follow-up. In cohort 2, we found there were no relationship between CSF and blood levels of TDP-43. Moreover, the levels of TDP-43 in CSF was positively associated with the age of patients, especially in AD group. Conclusion: Single blood TDP-43 could not estimate dementia occurrence; however, TDP-43 combined with demographics has the predictive effect for dementia occurrence and NfL level is associated with a decrease of cognitive function. Show more

Keywords: Dementia, follow-up, mild cognitive impairment, neurofilament light chain, TDP-43

DOI: 10.3233/JAD-201263

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 301-309, 2021

Authors: Soares, Jelena Zugic | Pettersen, Renate | Benth, Jūratė Šaltytė | Persson, Karin | Strobel, Carsten | Selbæk, Geir | Bogdanovic, Nenad

Article Type: Research Article

Abstract: Background: Allele ɛ 4 of the apolipoprotein (APOE ∈ 4) gene is the strongest known genetic risk factor for late-onset sporadic Alzheimer’s disease. A possible relationship between vitamin D and APOE is not yet clear. Objective: In this exploratory, cross-sectional study, we examined the association between serum levels of 25-hydroxyvitamin D [25(OH)D ] and brain volumes and the associations of both serum levels of 25(OH)D and APOE polymorphism to brain volumes in 127 persons (mean age 66 years) with cognitive symptoms. Methods: All subjects were examined with fully automated software for MRI volumetry, …NeuroQuant. Results: After adjustment for relevant covariates, higher serum 25(OH)D levels were associated with greater volumes of cortical gray matter on both left (p  = 0.02) and right (p  = 0.04) sides. When both 25(OH)D levels and APOE genotype were used as the main covariates, no significant associations were found between vitamin D level and brain volume in any of the 11 brain regions. In adjusted models, only homozygous but not heterozygous APOE ∈ 4 allele carriers had significantly larger inferior lateral ventricles (p  = 0.003) and smaller hippocampal volume (p  = 0.035) than those without ɛ 4. Homozygous APOE ∈ 4 carriers also had significantly higher vitamin D levels (p  = 0.009) compared to persons without the APOE ∈ 4 allele. Conclusion: Higher vitamin D levels might have a preserving effect on cortical grey matter volume. Show more

Keywords: APOE , brain volumetry, dementia, executive function, grey matter volume, vitamin D

DOI: 10.3233/JAD-201018

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 311-321, 2021

Authors: Deniz, Kaancan | Ho, Charlotte C.G. | Malphrus, Kimberly G. | Reddy, Joseph S. | Nguyen, Thuy | Carnwath, Troy P. | Crook, Julia E. | Lucas, John A. | Graff-Radford, Neill R. | Carrasquillo, Minerva M. | Ertekin-Taner, Nilüfer

Article Type: Research Article

Abstract: Background/Objective: The aim of this study was to determine if plasma concentrations of 5 surrogate markers of Alzheimer’s disease (AD) pathology and neuroinflammation are associated with disease status in African Americans. Methods: We evaluated 321 African Americans (159 AD, 162 controls) from the Florida Consortium for African-American Alzheimer’s Disease Studies (FCA3 DS). Five plasma proteins reflecting AD neuropathology or inflammation (Aβ42 , tau, IL6, IL10, TNFα ) were tested for associations with AD, age, sex, APOE and MAPT genotypes, and for pairwise correlations. Results: Plasma tau levels were higher in AD when adjusted for …biological and technical covariates. APOE ɛ 4 was associated with lower plasma Aβ42 and tau levels. Older age was associated with higher plasma Aβ42 , tau, and TNFα . Females had lower IL10 levels. Inflammatory proteins had strong pairwise correlations amongst themselves and with Aβ42 . Conclusion: We identified effects of demographic and genetic variants on five potential plasma biomarkers in African Americans. Plasma inflammatory biomarkers and Aβ42 may reflect correlated pathologies and elevated plasma tau may be a biomarker of AD in this population. Show more

Keywords: African Americans, Alzheimer’s disease, biomarkers, minority health

DOI: 10.3233/JAD-200828

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 323-334, 2021

Authors: Stojakovic, Andrea | Chang, Su-Youne | Nesbitt, Jarred | Pichurin, Nicholas P. | Ostroot, Mark A. | Aikawa, Tomonori | Kanekiyo, Takahisa | Trushina, Eugenia

Article Type: Research Article

Abstract: Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer’s disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD …mice from 3.5–18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synaptic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD. Show more

Keywords: 3xTg-AD transgenic mice, Alzheimer’s disease, electrophysiology, fluorodeoxyglucose F18 positron-emission tomography, human tau protein, mitochondrial complex I, small molecule therapeutics

DOI: 10.3233/JAD-201015

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 335-353, 2021

Authors: Kuske, Silke | Borgmann, Sandra Olivia | Wolf, Florian | Bleck, Christian

Article Type: Research Article

Abstract: Background: Current research acknowledges the relevance of the emotional safety of people living with dementia. However, available evidence regarding this topic is limited. A comprehensive view of this topic that equally considers the perspectives of people living in an early stage of dementia, relatives, and public stakeholders is lacking. Objective: This study aimed to obtain a multiperspective view of emotional safety in the context of dementia in the living environment. Methods: A descriptive qualitative study was conducted based on data collected through semi-structured guided interviews (n  = 14), focus groups (n  = 3), guided feedback, and participatory approaches. …People living in an early stage of dementia (N = 6), relatives of people living with dementia (N = 11), and public stakeholders (N = 15) were included. Results: Considering “social togetherness”, “personal condition”, “health”, “physical environment”, and “society” in the light of “living and learning in relations” are preconditions for understanding emotional safety in the context of dementia. “Living and learning in relations” refers to the interaction of people in the context of dementia and relations to the topic of dementia. The focus lies on the (collective) learning. The individuality of each person and his or her situation is central, related to dementia-related, psychosocial, biographical, physical, and economic factors. Conclusion: Our study highlights the relevance of research on emotional safety in the context of dementia. Approaches to improving the emotional safety of people living in an early stage of dementia should consider the complex situations of each target group in relation to each other at the micro, meso, and macro levels. Show more

Keywords: Alzheimer’s disease, dementia, emotion, patient safety, qualitative research, safety

DOI: 10.3233/JAD-201110

Citation: Journal of Alzheimer's Disease, vol. 79, no. 1, pp. 355-375, 2021