Journal of Alzheimer's Disease - Volume 75, issue 3

Authors: Ayton, Darshini | Gardam, Madeleine | Ward, Stephanie | Brodaty, Henry | Pritchard, Elizabeth | Earnest, Arul | Krysinska, Karolina | Banaszak-Holl, Jane | McNeil, John | Ahern, Susannah

Article Type: Research Article

Abstract: Background: A clinical quality registry (CQR) for dementia provides benefits to those living with dementia and their carers by improving the quality and experience of care through benchmarking and monitoring patient outcomes. CQRs use data collected to form clinical quality indicators (CQIs) through which variations in clinical processes and outcomes between different services and jurisdictions can be highlighted. Objective: This modified Delphi study aimed to develop CQIs for a pilot Australian CQR for dementia and mild cognitive impairment. These CQIs are based on evidence, patient and caregiver experience, and clinician perspectives across the trajectory of care from diagnosis …to end-of-life. Methods: An initial list of indicators from existing dementia registries, academic literature, and clinical practice guidelines was synthesized. A working group of clinicians and registry experts further refined these indicators. A panel of experts comprised of a consumer, a carer, clinicians, consumer organization representatives, and academics. The experts participated in three phases of the modified Delphi study: 1) online survey for scoring importance and validity, 2) a one-day face-to-face discussion, and 3) final survey round to assess importance, validity, and feasibility. Results: The panel assessed 33 CQIs and confirmed a final set of 18 indicators. The CQIs mapped to the domains of quality of diagnosis, quality of management, access to services and supports, and potentially preventable complications. These CQIs will be tested initially in memory clinics and inform the data collection processes for the Australia Dementia Network Registry (ADNet). Conclusion: A dementia CQR is fundamental to ongoing monitoring and development of good quality and consistent care across Australia. Show more

Keywords: Alzheimer’s disease, clinical quality registry, dementia, modified Delphi study

DOI: 10.3233/JAD-191044

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 923-936, 2020

Authors: Manniche, Christina | Simonsen, Anja Hviid | Hasselbalch, Steen Gregers | Andreasson, Ulf | Zetterberg, Henrik | Blennow, Kaj | Høgh, Peter | Juhler, Marianne | Hejl, Anne-Mette

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) remains a challenge to differentiate from subcortical ischemic vascular disease (SIVD). Despite major research efforts, the cerebrospinal fluid (CSF) biomarker profiles of the two diseases are still not known in detail. Objective: To determine if novel CSF biomarkers, neurofilament light (NFL) reflecting axonal damage, the synaptic protein neurogranin (NG), and the astroglial marker chitinase-3-like protein 1 (YKL-40), and the core Alzheimer’s disease (AD) biomarkers, amyloid-β 42 (Aβ42 ), total tau (t-tau), phosphorylated tau (p-tau), can differentiate iNPH from SIVD. Patients with AD and healthy controls (HC) were included for comparison purposes. …Methods: Patients with iNPH (n  = 28), SIVD (n  = 30), AD (n  = 57), and HC (n  = 33) were retrospectively included from the Danish Dementia Biobank. All patients with iNPH had effect of shunt surgery with a follow-up period of 4 to 69 months. CSF biomarkers were measured using immunoassays. Results: Lower levels of NFL, NG, Aβ42 , and t-tau were found in patients with iNPH versus SIVD, while YKL-40 and p-tau were similar in the two diseases. NFL and Aβ42 were the most reliable biomarkers to differentiate iNPH from SIVD with an area under the curve (AUC) on 0.82 and 0.80, respectively. Combining NFL with Aβ42 , t-tau, and p-tau resulted in an AUC of 0.90, which was equivalent to the diagnostic accuracy of all six biomarkers combined. Conclusion: An addition of NFL to the CSF panel of Aβ42 , t-tau, and p-tau may improve the differentiation of iNPH from SIVD. Show more

Keywords: Biomarkers, cerebrospinal fluid, normal pressure hydrocephalus, vascular dementia

DOI: 10.3233/JAD-200036

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 937-947, 2020

Authors: Lim, Ho Jae | Park, Jung Eun | Kim, Byeong C. | Choi, Seong-Min | Song, Min-Kyung | Cho, Soo Hyun | Seo, Hyeon Jeong | Kim, Jahae | Song, Ho-Chun | Choi, Kyu Yeong | Lee, Jang Jae | Kim, Hoo-Won | Ha, Jung-Min | Song, Woo Keun | Park, Sung-Gyoo | Lee, Jung Sup | Lee, Kun Ho

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) amyloid-β1-42 (Aβ1-42 ), total tau protein (t-Tau), and phosphorylated Tau (p-Tau) are ATN biomarkers for Alzheimer’s disease (AD) and reflect pathogenic changes in the brain. CSF biomarkers of AD are considered for inclusion in the diagnostic criteria for research and clinical purposes to reduce the uncertainty of clinical diagnosis and to distinguish among AD stages. Objective: This study aims to compare two commercially available analytical platforms with respect to accuracy and the potential for early diagnosis of AD. Methods: A total of 211 CSF samples from healthy control (HC) and AD …subjects were analyzed using two analytical platforms, INNOTEST ELISA and INNOBIA AlzBio3 xMAP kits. The accuracy of diagnosis and AUC values distinguishing study groups were compared between the two analytical platforms. Results: The absolute values for Aβ1-42 , t-Tau, and p-Tau181 levels differed between the two platforms. The Aβ1-42 levels decreased, while t-Tau and p-Tau levels increased according to the AD stages. The AUC of Aβ1-42 and t-Tau, which distinguish the early stages of AD (preclinical and prodromal AD), were similar between the two platforms, whereas there were significant differences in p-Tau AUC values. CSF p-Tau using the INNOBIA was highly accurate for distinguishing both preclinical AD (AUC = 0.826, cut-off score≥38.89) and prodromal AD (AUC = 0.862, cut-off score≥41.88) from HC. Conclusion: The accuracy of CSF p-Tau levels in the preclinical and prodromal AD is higher for the INNOBIA than the INNOTEST, and the early stage AD can be accurately distinguished from HC. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, immunoassay, preclinical AD, tau protein

DOI: 10.3233/JAD-191331

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 949-958, 2020

Authors: Callahan, Christopher M. | Apostolova, Liana G. | Gao, Sujuan | Risacher, Shannon L. | Case, Jamie | Saykin, Andrew J. | Lane, Kathleen A. | Swinford, Cecily G. | Yoder, Mervin C.

Article Type: Research Article

Abstract: Background: Aberrant angiogenesis may play a role in the development of Alzheimer’s disease and related dementia. Objective: To explore the relationship between angiogenesis activity and evidence of neurodegeneration among older adults. Methods: Cross-sectional study of 49 older adults clinically characterized as cognitively normal, mild cognitive impairment, or early Alzheimer’s disease. In addition to neuroimaging, we completed assays on peripheral blood, including: vascular endothelial growth factor, tumor necrosis factor, fibroblast growth factor, and amyloid-β peptide 40. We used advanced polychromatic flow cytometry to phenotype circulating mononuclear cells to assess angiogenesis activity. Results: Although we documented …differences in cognitive performance, structural changes on neuroimaging, and burden of amyloid and tau on positron emission tomography, angiogenesis activity did not vary by group. Interestingly, VEGF levels were shown to be increased among subjects with mild cognitive impairment. In ANCOVA models controlling for age, sex, intracranial volume, and monocyte subpopulations, angiogenesis activity was correlated with increased white matter hyperintensities. Conclusion: We demonstrate a significant association between angiogenesis activity and cerebrovascular disease. To better understand the potential of angiogenesis as an intervention target, longitudinal studies are needed. Show more

Keywords: Alzheimer’s disease, biomarkers, pathologic angiogenesis, vascular dementia

DOI: 10.3233/JAD-191293

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 959-969, 2020

Authors: Dong, Qunxi | Zhang, Jie | Li, Qingyang | Wang, Junwen | Leporé, Natasha | Thompson, Paul M. | Caselli, Richard J. | Ye, Jieping | Wang, Yalin | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Disease progression prediction based on neuroimaging biomarkers is vital in Alzheimer’s disease (AD) research. Convolutional neural networks (CNN) have been proved to be powerful for various computer vision research by refining reliable and high-level feature maps from image patches. Objective: A key challenge in applying CNN to neuroimaging research is the limited labeled samples with high dimensional features. Another challenge is how to improve the prediction accuracy by joint analysis of multiple data sources (i.e., multiple time points or multiple biomarkers). To address these two challenges, we propose a novel multi-task learning framework based on CNN. …Methods: First, we pre-trained CNN on the ImageNet dataset and transferred the knowledge from the pre-trained model to neuroimaging representation. We used this deep model as feature extractor to generate high-level feature maps of different tasks. Then a novel unsupervised learning method, termed Multi-task Stochastic Coordinate Coding (MSCC), was proposed for learning sparse features of multi-task feature maps by using shared and individual dictionaries. Finally, Lasso regression was performed on these multi-task sparse features to predict AD progression measured by the Mini-Mental State Examination (MMSE) and the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-Cog). Results: We applied this novel CNN-MSCC system on the Alzheimer’s Disease Neuroimaging Initiative dataset to predict future MMSE/ADAS-Cog scales. We found our method achieved superior performances compared with seven other methods. Conclusion: Our work may add new insights into data augmentation and multi-task deep model research and facilitate the adoption of deep models in neuroimaging research. Show more

Keywords: Alzheimer’s disease, convolutional neural networks, dictionary learning, multi-task learning, transfer learning

DOI: 10.3233/JAD-190973

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 971-992, 2020

Authors: Fiala, Milan | Lau, Yik Chai Charles | Aghajani, Anthony | Bhargava, Sneha | Aminpour, Eli | Kaczor-Urbanowicz, Karolina Elżbieta | Mirzoyan, Hayk | Nichols, India | Ko, Meng-Wei | Morselli, Marco | Santana, Joslyn | Dang, Johnny | Sayre, James | Paul, Ketema | Pellegrini, Matteo

Article Type: Research Article

Abstract: Background: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer’s disease (AD) are palliative for a limited time. Objective: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. Methods: We performed a prospective study using Mini-Mental State Examination, amyloid-β (Aβ) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies …(DLB) patients. Results: MCI, FTD, and DLB patients patients volunteered for the addition of a ω -3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aβ phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitro ω -3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. Conclusion: Add-on ω -3 therapy to CI may delay dementia in certain patients who had failed single CI therapy. Show more

Keywords: Amyloid-beta, bioenergy, cell signaling, cholinesterase inhibitor, glycolysis, ω-3 fatty acids, phagocytosis, tricarboxylic cycle

DOI: 10.3233/JAD-200252

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 993-1002, 2020

Authors: Iaccarino, Leonardo | Sala, Arianna | Caminiti, Silvia Paola | Presotto, Luca | Perani, Daniela | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by an involvement of brain dopamine (DA) circuitry, the presence of which has been associated with emergence of both neuropsychiatric symptoms and cognitive deficits. Objective: In order to investigate whether and how the DA pathways are involved in the pathophysiology of AD, we assessed by in vivo neuroimaging the structural and metabolic alterations of subcortical and cortical DA pathways and targets. Methods: We included 54 healthy control participants, 53 amyloid-positive subjects with mild cognitive impairment due to AD (MCI-AD), and 60 amyloid-positive patients with probable dementia due to AD …(ADD), all with structural 3T MRI and 18 F-FDG-PET scans. We assessed MRI-based gray matter reductions in the MCI-AD and ADD groups within an anatomical a priori -defined Nigrostriatal and Mesocorticolimbic DA pathways, followed by 18 F-FDG-PET metabolic connectivity analyses to evaluate network-level metabolic connectivity changes. Results: We found significant tissue loss in the Mesocorticolimbic over the Nigrostriatal pathway. Atrophy was evident in the ventral striatum, orbitofrontal cortex, and medial temporal lobe structures, and already plateaued in the MCI-AD stage. Degree of atrophy in Mesocorticolimbic regions positively correlated with the severity of depression, anxiety, and apathy in MCI-AD and ADD subgroups. Additionally, we observed significant alterations of metabolic connectivity between the ventral striatum and fronto-cingulate regions in ADD, but not in MCI-AD. There were no metabolic connectivity changes within the Nigrostriatal pathway. Conclusion: Our cross-sectional data support a clinically-meaningful, yet stage-dependent, involvement of the Mesocorticolimbic system in AD. Longitudinal and clinical correlation studies are needed to further establish the relevance of DA system involvement in AD. Show more

Keywords: Alzheimer’s disease, connectivity, dementia, dopamine systems, mild cognitive impairment, ventro-tegmental area

DOI: 10.3233/JAD-190954

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1003-1016, 2020

Authors: Broulikova, Hana Marie | Arltova, Marketa | Kuklova, Marie | Formanek, Tomas | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Facing an increasing prevalence of dementia, the Czech Republic is developing a new nationwide strategy for the management and prevention of dementia. Lack of evidence about characteristics of individuals with dementia in the country is a major obstacle. Objective: The study aimed to 1) characterize individuals with dementia, 2) compare their mortality with the general population, and 3) analyze differences in survival between different dementia disorders. Methods: The study capitalizes on two nationwide registers in the Czech Republic, from which information about individuals who were hospitalized with dementia or died from it between 1994 and …2014 was retrieved. Standardized intensity of hospitalizations was calculated for each year, mortality was studied using standardized mortality ratio, life-tables, Kaplan-Mayer curves, and Cox proportional hazard models. Results: Standardized intensity of hospitalizations for dementia increased more than 3 times from 1994 to 2014. Standardized mortality ratio was 3.03 (95% confidence interval 2.97–3.08). One-year survival rate was 45% and five-year survival rate 16%. Vascular dementia was the most common type of dementia disorders and was associated with higher hazard of death than Alzheimer’s disease, even after adjusting for sociodemographic and clinical covariates (hazard ratio 1.04; 95% confidence interval 1.02–1.05). Conclusion: The study provides estimates on demographic characteristics and mortality of the Czech hospitalized dementia population, which have not been so far available and which are unique also in the context of the entire region of Central and Eastern Europe. Show more

Keywords: Alzheimer’s disease, Czech Republic, dementia, hospitalization, mortality, population characteristics, registries

DOI: 10.3233/JAD-191117

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1017-1027, 2020

Authors: Babić Leko, Mirjana | Nikolac Perković, Matea | Klepac, Nataša | Štrac, Dubravka Švob | Borovečki, Fran | Pivac, Nela | Hof, Patrick R. | Šimić, Goran

Article Type: Research Article

Abstract: Background: Neuroinflammation plays an important role in Alzheimer’s disease (AD). During this process, activated microglia release pro-inflammatory cytokines such as interleukin (IL)-1α , IL-1β, IL-6, and tumor necrosis factor α (TNFα ) that participate in neuron damage, but also anti-inflammatory cytokines (such as IL-10), which maintain homeostasis of immune response. Previous studies showed the association of IL-1 α –889C/T (rs1800587), IL-1 β–1473G/C (rs1143623), IL-6 –174C/G (rs1800795), IL-10 –1082G/A (rs1800896), and TNF α –308A/G (rs1800629) polymorphisms with AD. Objective: We aimed to investigate whether people with certain IL-1 α , IL-1 β, IL-6 , …IL-10 , and TNF α genotypes in these polymorphisms are more prone to develop AD-related pathology, reflected by pathological levels of cerebrospinal fluid (CSF) AD biomarkers including amyloid-β1-42 , total tau (t-tau), tau phosphorylated at Thr 181 (p-tau181 ), Ser 199 (p-tau199 ), and Thr 231 (p-tau231 ), and visinin-like protein 1 (VILIP-1). Methods: The study included 115 AD patients, 53 patients with mild cognitive impairment, and 11 healthy controls. The polymorphisms were determined using real-time polymerase chain reaction. Levels of CSF biomarkers were determined by enzyme-linked immunosorbent assay. Results: A significant increase in p-tau CSF levels was found in patients with the AA IL-10 –1082G/A and GG TNF α –308A/G genotypes, and in carriers of a G allele in IL-1 β –1473C/G and IL-6 –174C/G polymorphisms. t-tau levels were increased in carriers of a G allele in IL-1 β –1473C/G polymorphism. An increase in VILIP-1 levels was observed in patients with CG and GG IL-1 β –1473C/G, GC IL-6 –174C/G, and GG TNF α –308A/G genotype. Conclusion: These results suggest that persons carrying certain genotypes in IL10 (–1082G/A), IL1 β (1473C/G), IL6 (–174C/G), and TNFIα (–308A/G) could be more vulnerable to development of neuroinflammation, and consequently of AD. Show more

Keywords: Alzheimer’s disease, biomarkers, IL-10, IL-1, IL-6, inflammation, polymorphisms, TNFα

DOI: 10.3233/JAD-200056

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1029-1047, 2020

Authors: Torres, Stephanie | Alexander, Angel | O’Bryant, Sid | Medina, Luis D.

Article Type: Research Article

Abstract: Background: Various factors, such as age, cardiovascular concerns, and lifestyle patterns, are associated with risk for cognitive decline and Alzheimer’s disease (AD). Risk scores model predictive risk of developing a disease (e.g., dementia, stroke). Many of these scores have been primarily developed in largely non-Hispanic/Latino (non-H/L) White samples and little is known about their applicability in ethno-racially diverse populations. Objective: The primary aim was to examine the relationship between three established risk scores and cognitive performance. These relationships were compared across ethnic groups. Methods: We conducted a cross-sectional study with a multi-ethnic, rural-dwelling group of participants …(M age  = 61.6±12.6 years, range: 40–96 years; 373F:168M; 39.7% H/L). The Cardiovascular Risk Factors, Aging and Dementia (CAIDE), Framingham Risk Score (FRS), and Washington Heights-Inwood Columbia Aging Project (WHICAP) score were calculated for each participant. Results: All three scores were significantly associated with cognition in both H/L and non-H/L groups. In H/Ls, cognition was predicted by FRS: β= –0.08, p  = 0.022; CAIDE: β= –0.08, p  < 0.001; and WHICAP: β= –0.04, p  < 0.001. In non-H/Ls, cognition was predicted by FRS: β= –0.11, p  < 0.001; CAIDE: β= –0.14, p  < 0.001; and WHICAP: β= –0.08, p  < 0.001. The strength of this relationship differed between groups for FRS [t(246) = –4.61, p  < 0.001] and CAIDE [t(420) = –3.20, p  = 0.001], but not for WHICAP [t(384) = –1.03, p  = 0.30], which already includes ethnicity in its calculation. Conclusion: These findings support the utility of these three risk scores in predicting cognition while underscoring the need to account for ethnicity. Moreover, our results highlight the importance of cardiovascular and other demographic factors in predicting cognitive outcomes. Show more

Keywords: Aging, cognition, dementia, Hispanic Americans, minority health

DOI: 10.3233/JAD-191284

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1049-1059, 2020