Journal of Alzheimer's Disease - Volume 83, issue 2

Authors: Thorlacius-Ussing, Gorm | Bruun, Marie | Gjerum, Le | Frederiksen, Kristian S. | Rhodius-Meester, Hanneke F.M. | van der Flier, Wiesje M. | Waldemar, Gunhild | Hasselbalch, Steen G.

Article Type: Research Article

Abstract: Background: Evidence-based recommendations on the optimal evaluation approach for dementia diagnostics are limited. This impedes a harmonized workup across clinics and nations. Objective: To evaluate the diagnostic performance of a multidisciplinary consensus conference compared to a single clinician approach. Methods: In this prospective study, we enrolled 457 patients with suspected cognitive decline, from two European memory clinics. A diagnostic evaluation was performed at baseline independently in two ways: 1) by a single clinician and 2) at a multidisciplinary consensus conference. A syndrome diagnosis and an etiological diagnosis was made. The confidence in the diagnosis was recorded …using a visual analogue scale. An expert panel re-evaluation diagnosis served as reference for the baseline syndrome diagnosis and a 12-24-month follow-up diagnosis for the etiological diagnosis. Results: 439 patients completed the study. We observed 12.5%discrepancy (k  = 0.81) comparing the baseline syndrome diagnoses of the single clinician to the consensus conference, and 22.3%discrepancy (k  = 0.68) for the baseline etiological diagnosis. The accuracy of the baseline etiological diagnosis was significantly higher at the consensus conference and was driven mainly by increased accuracy in the MCI group. Confidence in the etiological diagnosis at baseline was significantly higher at the consensus conference (p  < 0.005), especially for the frontotemporal dementia diagnosis. Conclusion: The multidisciplinary consensus conference performed better on diagnostic accuracy of disease etiology and increased clinicians’ confidence. This highlights the importance of a multidisciplinary diagnostic evaluation approach for dementia diagnostics, especially when evaluating patients in the MCI stage. Show more

Keywords: Alzheimer disease, clinical decision-making, dementia, differential diagnosis, frontotemporal dementia, Lewy body disease, vascular dementia

DOI: 10.3233/JAD-210278

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 741-751, 2021

Authors: Rasmussen, Ingrid Daae | Boayue, Nya Mehnwolo | Mittner, Matthias | Bystad, Martin | Grønli, Ole K. | Vangberg, Torgil Riise | Csifcsák, Gábor | Aslaksen, Per M.

Article Type: Research Article

Abstract: Background: The optimal stimulation parameters when using transcranial direct current stimulation (tDCS) to improve memory performance in patients with Alzheimer’s disease (AD) are lacking. In healthy individuals, inter-individual differences in brain anatomy significantly influence current distribution during tDCS, an effect that might be aggravated by variations in cortical atrophy in AD patients. Objective: To measure the effect of individualized HD-tDCS in AD patients. Methods: Nineteen AD patients were randomly assigned to receive active or sham high-definition tDCS (HD-tDCS). Computational modeling of the HD-tDCS-induced electric field in each patient’s brain was analyzed based on magnetic resonance imaging …(MRI) scans. The chosen montage provided the highest net anodal electric field in the left dorsolateral prefrontal cortex (DLPFC). An accelerated HD-tDCS design was conducted (2 mA for 3×20 min) on two separate days. Pre- and post-intervention cognitive tests and T1 and T2-weighted MRI and diffusion tensor imaging data at baseline were analyzed. Results: Different montages were optimal for individual patients. The active HD-tDCS group improved significantly in delayed memory and MMSE performance compared to the sham group. Five participants in the active group had higher scores on delayed memory post HD-tDCS, four remained stable and one declined. The active HD-tDCS group had a significant positive correlation between fractional anisotropy in the anterior thalamic radiation and delayed memory score. Conclusion: HD-tDCS significantly improved delayed memory in AD. Our study can be regarded as a proof-of-concept attempt to increase tDCS efficacy. The present findings should be confirmed in larger samples. Show more

Keywords: Alzheimer’s disease, computational modeling, NIBS, noninvasive brain stimulation, tDCS, transcranial direct current stimulation

DOI: 10.3233/JAD-210378

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 753-769, 2021

Authors: Matias-Guiu, Jordi A. | Pytel, Vanesa | Hernández-Lorenzo, Laura | Patel, Nikil | Peterson, Katie A. | Matías-Guiu, Jorge | Garrard, Peter | Cuetos, Fernando

Article Type: Research Article

Abstract: Background: Primary progressive aphasia (PPA) is a neurodegenerative syndrome with three main clinical variants: non-fluent, semantic, and logopenic. Clinical diagnosis and accurate classification are challenging and often time-consuming. The Mini-Linguistic State Examination (MLSE) has been recently developed as a short language test to specifically assess language in neurodegenerative disorders. Objective: Our aim was to adapt and validate the Spanish version of MLSE for PPA diagnosis. Methods: Cross-sectional study involving 70 patients with PPA and 42 healthy controls evaluated with the MLSE. Patients were independently diagnosed and classified according to comprehensive cognitive evaluation and advanced neuroimaging. …Results: Internal consistency was 0.758. The influence of age and education was very low. The area under the curve for discriminating PPA patients and healthy controls was 0.99. Effect sizes were moderate-large for the discrimination between PPA and healthy controls. Motor speech, phonology, and semantic subscores discriminated between the three clinical variants. A random forest classification model obtained an F1-score of 81%for the three PPA variants. Conclusion: Our study provides a brief and useful language test for PPA diagnosis, with excellent properties for both clinical routine assessment and research purposes. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, neuropsychological, primary progressive aphasia

DOI: 10.3233/JAD-210668

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 771-778, 2021

Authors: He, Haining | Liu, An | Zhang, Wei | Yang, Huanqing | Zhang, Minmin | Xu, Hua | Liu, Yuanyuan | Hong, Bo | Yan, Feng | Yue, Ling | Wang, Jinghua | Xiao, Shifu | Xie, Zuoquan | Wang, Tao

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is a prodromal stage of Alzheimer’s disease (AD) involving imbalanced beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). MicroRNAs (miRNAs) are associated with AD. Objective: This study aimed to investigated whether plasma miRNAs can predict prodromal AD or are associated with AD pathology. Methods: Participants in the discovery set (n  = 10), analysis set (n  = 30), and validation set (n  = 80) were screened from the China Longitudinal Aging Study. RNA was extracted from the participants’ plasma. Microarray sequencing provided miRNA profiles and differentially expressed miRNAs (DEmiRNAs) in the discovery set included …patients with 18 F-Flutemetamol positron emission tomography scan-confirmed aMCI. Potential biomarkers were screened in the analysis set. The predict capability of candidate miRNAs was assessed in the validation set. Candidate miRNAs modulation of BACE1 expression was explored in rat and human hippocampal neurons in vitro . Results: We verified 46 significant DEmiRNAs between the aMCI and NC groups (p  < 0.05), among which 33 were downregulated. In the analysis set, miR-1185-2-3p, miR-1909-3p, miR-22-5p, and miR-134-3p levels decreased significantly in the aMCI group. These miRNAs and previously identified miR-107 were selected as potential biomarkers. A prediction model comprising these five miRNAs showed outstanding accuracy (81.25%) to discriminate aMCI at cut-off value of 0.174. Except for miR-134-3p, the other four miRNAs significantly suppressed Bace1 expression in rat hippocampal neurons in vitro . BACE1 modulation of miR-1185-2-3p, miR-1909-3p, and miR-134-3p was confirmed in human hippocampal neurons in vitro . Conclusion: A predictive model consisting of five BACE1-related plasma miRNAs could be a novel biomarker for aMCI. Show more

Keywords: Alzheimer’s disease, biomarkers, microRNAs, mild cognitive impairment

DOI: 10.3233/JAD-210307

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 779-790, 2021

Authors: Wammes, Joost D. | Nakanishi, Miharu | van der Steen, Jenny T. | MacNeil Vroomen, Janet L.

Article Type: Research Article

Abstract: Background: Japan has one of the highest percentages of persons with dementia and hospital deaths in the world. Hospitals are often not equipped to handle the care complexity required for persons with dementia at the end of life. The National Dementia Orange plan aimed to decrease hospital deaths by expanding time in the community. Objective: The aim of this study is to evaluate whether the National Dementia Orange Plan is associated with a decrease in hospitals deaths for persons with dementia. Methods: We used quarterly, cross-sectional, national death certificate data consisting of the total Japanese dementia …population 65 years and older, spanning a period from 2009 to 2016. The primary outcome was quarterly adjusted relative risk rates (aRRR) of dying in hospital, nursing home, home, or elsewhere. An interrupted time series analysis was performed to study the slope change over time. Analyses were adjusted for sex and seasonality. Results: 149,638 died with dementia. With the implementation of the Orange Plan, death in nursing home (aRRR 1.08, [1.07–1.08], p  < 0.001) and elsewhere (aRRR 1.05, [1.05–1.06], p  < 0.001) increased over time compared to hospital death. No changes were found in death at home. Conclusion: This study provides evidence that the National Dementia Orange plan was associated with a small increase in death in nursing home and elsewhere. Hospital death remained the primary location of death. End-of-life strategies should be expanded in national dementia policies to increase aging in the community until death. Show more

Keywords: Dementia, end-of-life, health policy, interrupted time series, Japan, place of death

DOI: 10.3233/JAD-210521

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 791-797, 2021

Authors: Cai, Hong-Yan | Yang, Dan | Qiao, Jing | Yang, Jun-Ting | Wang, Zhao-Jun | Wu, Mei-Na | Qi, Jin-Shun | Hölscher, Christian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a degenerative disorder, accompanied by progressive cognitive decline, for which there is no cure. Recently, the close correlation between AD and type 2 diabetes mellitus (T2DM) has been noted, and a promising anti-AD strategy is the use of anti-T2DM drugs. Objective: To investigate if the novel glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist DA4-JC shows protective effects in the triple APP/PS1/tau mouse model of AD. Methods: A battery of behavioral tests were followed by in vivo recording of long-term potentiation (LTP) in the hippocampus, quantified synapses using the …Golgi method, and biochemical analysis of biomarkers. Results: DA4-JC improved cognitive impairment in a range of tests and relieved pathological features of APP/PS1/tau mice, enhanced LTP in the hippocampus, increased numbers of synapses and dendritic spines, upregulating levels of post-synaptic density protein 95 (PSD95) and synaptophysin (SYP), normalized volume and numbers of mitochondria and improving the phosphatase and tensin homologue induced putative kinase 1 (PINK1) - Parkin mitophagy signaling pathway, while downregulating amyloid, p-tau, and autophagy marker P62 levels. Conclusion: DA4-JC is a promising drug for the treatment of AD. Show more

Keywords: Alzheimer’s disease, cognitive impairment, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, type 2 diabetes mellitus

DOI: 10.3233/JAD-210256

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 799-818, 2021

Authors: Zhou, Jie | Ma, Luping | Zhao, Lulei | Sheng, Jiamin | Xu, Yuhua | Chen, Jie | Yu, Liangjun | Sun, Quan | Zhou, Hangyang | Zhu, Shaofeng | Lu, Zefeng | Wei, Bo

Article Type: Research Article

Abstract: Background: Nutritional status has been recognized as an important factor influencing cognitive function-related diseases, but few comprehensive nutrition indicators are available to assess the risk of cognitive decline. Objective: This study aimed to investigate the relationship between the prognostic nutritional index (PNI) and cognitive function in an elderly population, and the differences in nutrient intake between different levels of nutritional risk. Methods: Based on cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014, we included 2,564 older participants. The lower quartile of each of the four cognitive tests was considered to have cognitive …function impairment (CFI). Binary and multivariate logistic regression models were used to estimate the relationship between the PNI and the odds ratio of CFI. Results: After adjustment for confounding variables, we found that the odds of CFI were significantly lower for participants with normal PNI levels than for those with low PNI levels. In a comparison of global cognitive impairment scores, participants with a normal PNI had lower ratios of poor cognitive performance than those with a low PNI. By comparing the nutrient intake at different PNI levels, we found a reduction in the intake of protein, dietary fiber, total saturated fatty acids, and multiple micronutrients in the low PNI group. Conclusion: Our study shows that the PNI can be a good predictor of the odds of CFI in the elderly population and that it is a convenient indicator of reduced intake of nutrients which may be important to brain health. Show more

Keywords: Cognitive function impairment, malnutrition, national health and nutrition examination survey (NHANES), older adults, prognostic nutritional index

DOI: 10.3233/JAD-210141

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 819-831, 2021

Authors: Yu, Yang | Gao, Yang | Winblad, Bengt | Tjernberg, Lars O. | Schedin-Weiss, Sophia

Article Type: Research Article

Abstract: Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ42 ), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the fragments involved in the amyloidogenic pathway in primary neurons with a focus on Aβ42 and its immediate substrate AβPP C-terminal fragment (APP-CTF). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. …Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional three-channel imaging, and quantitative image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes in soma, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes. Lack of colocalization of Aβ42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons. Show more

Keywords: Aβ42, Alzheimer’s disease, amyloid-β protein precursor, stimulated emission depletion microscopy, synapse

DOI: 10.3233/JAD-215008

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 833-852, 2021

Authors: Sweigart, Benjamin | Andersen, Stacy L. | Gurinovich, Anastasia | Cosentino, Stephanie | Schupf, Nicole | Perls, Thomas T. | Sebastiani, Paola

Article Type: Research Article

Abstract: Background: The E4 allele of the APOE gene is known to be associated with cognitive impairment. However, a limited number of studies have examined the association between the E2 allele and longitudinal changes of cognitive function. Objective: To determine whether rates of cognitive change differ in carriers of the APOE E2 allele compared to other genotypes. Methods: We conducted a secondary analysis of data from two ongoing longitudinal cohort studies, the Long Life Family Study (LLFS) and New England Centenarian Study (NECS). We included participants who had APOE genotyping data, data from longitudinal …administrations of the Telephone Interview for Cognitive Status (TICS), and age, sex, and education available. We assessed whether cognitive change as measured by rate of decline in TICS score differed among people with different APOE genotypes. We used a hierarchical mixed effect model with APOE genotypes, their interactions with age, and potential confounders. Results: After adjusting for sex and education, in carriers of the common E3/E3 genotype, TICS score decreased by 0.15 points per year of age. In those with the E2/E2 genotype, TICS score decreased by 0.05 points per year of age, a significantly slower rate of decline (p  = 0.017). We observed no protective effect of the E2/E3 genotype on cognitive decline. Conclusion: These results suggest a protective effect of the E2/E2 genotype on a measure of global cognitive function. Show more

Keywords: Apolipoproteins E, cognitive aging, cognitive dysfunction, genetics

DOI: 10.3233/JAD-201205

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 853-860, 2021

Authors: Pudumjee, Shehroo B. | Lundt, Emily S. | Albertson, Sabrina M. | Machulda, Mary M. | Kremers, Walter K. | Jack Jr., Clifford R. | Knopman, David S. | Petersen, Ronald C. | Mielke, Michelle M. | Stricker, Nikki H.

Article Type: Research Article

Abstract: Background: Longitudinal, but not cross-sectional, cognitive testing is one option proposed to define transitional cognitive decline for individuals on the Alzheimer’s disease continuum. Objective: Compare diagnostic accuracy of cross-sectional subtle objective cognitive impairment (sOBJ) and longitudinal objective decline (Δ OBJ) over 30 months for identifying 1) cognitively unimpaired participants with preclinical Alzheimer’s disease defined by elevated brain amyloid and tau (A+T+) and 2) incident mild cognitive impairment (MCI) based on Cogstate One Card Learning (OCL) accuracy performance. Methods: Mayo Clinic Study of Aging cognitively unimpaired participants aged 50 + with amyloid and tau PET scans (n  = 311) comprised …the biomarker-defined sample. A case-control sample of participants aged 65 + remaining cognitively unimpaired for at least 30 months included 64 who subsequently developed MCI (incident MCI cases) and 184 controls, risk-set matched by age, sex, education, and visit number. sOBJ was assessed by OCL z-scores. Δ OBJ was assessed using within subjects’ standard deviation and annualized change from linear regression or linear mixed effects (LME) models. Concordance measures Area Under the ROC Curve (AUC) or C-statistic and odds ratios (OR) from conditional logistic regression models were derived. sOBJ and Δ OBJ were modeled jointly to compare methods. Results: sOBJ and Δ OBJ-LME methods differentiated A+T+ from A-T- (AUC = 0.64, 0.69) and controls from incident MCI (C-statistic = 0.59, 0.69) better than chance; other Δ OBJ methods did not. Δ OBJ-LME improved prediction of future MCI over baseline sOBJ (p  = 0.003) but not over 30-month sOBJ (p  = 0.09). Conclusion: Longitudinal decline did not offer substantial benefit over cross-sectional assessment in detecting preclinical Alzheimer’s disease or incident MCI. Show more

Keywords: Amyloid, biomarker, cognigram, memory, neuropsychology, reliable change index, sensitivity and specificity, tau, transitional cognitive decline, validity

DOI: 10.3233/JAD-210251

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 861-877, 2021