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

Authors: Wang, Chenchen | Huang, Xi | Tian, Sai | Huang, Rong | Guo, Dan | Lin, Hongyan | Wang, Jiaqi | Wang, Shaohua

Article Type: Research Article

Abstract: Background: Metabolic disorders, including insulin resistance, obesity, and hyperlipidemia occur frequently prior to hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and cause mild cognitive impairment (MCI). Objective: We investigated the involvement of resistin in these metabolic abnormalities contributes to MCI in patients with T2DM. Methods: A total of 138 hospitalized patients with T2DM were enrolled and categorized into MCI and non-MCI groups according to the Montreal Cognitive Assessment (MoCA) score. Metabolic indicators and cognitive state were assessed, and plasma resistin levels were determined by ELISA. Results: The resistin levels and homeostasis model …assessment of insulin resistance (HOMA-IR) scores of MCI and gender-stratified subgroups were significantly higher than those of controls without MCI (all p  < 0.01). Correlation analysis showed that the resistin level was negatively associated with majority of cognitive domains, e.g., MoCA (r  = –0.693, p  < 0.001) and Mini-Mental State Examination (r  = –0.571, p  < 0.001), and was related to HOMA-IR (r  = 0.667, p  < 0.001) but not to obesity and lipid indices. Multivariable regression analysis indicated that resistin (β = –0.675, p  < 0.001) and educational level (β = 0.177, p  = 0.003) were independent risk factors of MoCA in patients with T2DM. Conclusions: High plasma resistin levels portend the insulin resistance-related susceptibility to early cognitive decline in Chinese patients with T2DM. The involvement of this adipokine in other metabolic disorders leading to diabetic MCI and its clinical value for early disease screening must be further studied. Show more

Keywords: Alzheimer’s disease, insulin resistance, mild cognitive impairment, resistin, type 2 diabetes

DOI: 10.3233/JAD-200074

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 807-815, 2020

Authors: Sultana, Munira | Bryant, Dianne | Orange, J.B. | Beedie, Taylor | Montero-Odasso, Manuel

Article Type: Research Article

Abstract: Background: Exercise is beneficial to maintain balance. Wii Fit©, a video game-based exercise, offers an enjoyable way to exercise and is feasible for older adults with neurocognitive disorders (NCD). Objective: To evaluate the effects of Wii Fit© exercise training on the balance of older adults with NCD. Methods: Systematic review and meta-analysis of randomized control trials using Cochrane collaboration tools. The participants were older adults (60 years and over) with NCD. Balance was measured with Berg Balance Scale (BBS) and Timed Up and Go (TUG). Two reviewers independently searched, selected, extracted data, assessed risk of biases, …and determined the quality of evidence. Outcomes were evaluated using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). A meta-analysis was performed. Results: The literature search identified 522 source documents of which titles and abstracts were reviewed for 428 after removing 94 duplicates. The reviewers selected five studies out of 50 after a full text review. The overall effect of Wii Fit© exercise training on BBS was moderate, significant, and clinically meaningful (standardized mean difference [SMD] = 0.5 standard deviation [SD] [95% confidence interval CI] 0.08, 0.84]). No effect was observed with TUG scores (SMD = 0.00 SD [95% CI –0.44, 0.44]). The GRADE quality of evidence was very low. Conclusion: Wii Fit© exercise training has a positive effect on balance in older adults with NCD. However, further research with sufficient power is needed to evaluate its effectiveness. Show more

Keywords: Aged, neurocognitive disorders, postural balance, video games

DOI: 10.3233/JAD-191301

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 817-826, 2020

Authors: Kaur, Gurjeet | Poljak, Anne | Braidy, Nady | Crawford, John D. | Lo, Jessica | Sachdev, Perminder S.

Article Type: Research Article

Abstract: Background: Numerous studies have reported on cerebrospinal fluid (CSF) and blood biomarkers of Alzheimer’s disease (AD); however, to date, none has compared biomarker patterns across the early-onset subtypes, i.e., early onset sporadic AD (EOsAD) and autosomal dominant AD (ADAD), qualitatively and quantitatively. Objective: To compare the fluid biomarker patterns in early-onset subtypes of AD; EOsAD and ADAD. Methods: Six scientific databases were searched for peer-reviewed research publications. The total number of individuals used in all the meta-analysis were 2,427, comprised of 1,337 patients and 1,090 controls. Results: In the subset of EOsAD cases without …APP , PSEN1 /PSEN2 mutations, CSF Aβ42 and tau levels were higher when compared to the EOsAD group as a whole. Prevalence of the APOE ɛ 4 allele was more elevated in EOsAD relative to controls, and not significantly elevated in ADAD cases. Conclusion: Established CSF biomarkers confirmed quantitative differences between variants of EOAD. EOsAD is enriched with APOE ɛ 4, but the level is not higher than generally reported in late-onset AD. The results prompt further exploration of the etiopathogenesis of EOsAD, which accounts for ∼4–10% of all AD cases, but the reasons for the early onset remain poorly understood. Show more

Keywords: Amyloid-β42 , APOE ɛ4, APP/PSEN, early onset Alzheimer’s disease, neurodegeneration biomarkers, tau

DOI: 10.3233/JAD-200052

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 827-843, 2020

Authors: Devanand, D. P. | Liu, Xinhua | Chunga, Richard E. | Cohen, Hannah | Andrews, Howard | Schofield, Peter W. | Stern, Yaakov | Huey, Edward D. | Choi, Jongwoo | Pelton, Gregory H.

Article Type: Research Article

Abstract: Background: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer’s disease (AD) pathology, and short-term change in odor identification impairment with cholinesterase inhibitor (CheI) treatment may predict longer term cognitive outcomes. Objective: In patients with mild cognitive impairment (MCI) treated prospectively with donepezil, a CheI, for 52 weeks, to determine if 1) acute decline in odor identification ability with anticholinergic challenge can predict cognitive improvement, and 2) change in odor identification over 8 weeks can predict cognitive improvement. Methods: MCI was diagnosed clinically without AD biomarkers. At baseline, the University of Pennsylvania Smell identification Test …(UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5 mg daily, increased to 10 mg daily if tolerated, and this dose was maintained for 52 weeks. Main outcomes were ADAS-Cog total score and Selective Reminding Test (SRT) total immediate recall score measured at baseline, 26 and 52 weeks. Results: In 100 study participants, mean age 70.14 (SD 9.35) years, atropine-induced decrease in UPSIT score at baseline was not associated with change in ADAS-Cog or SRT scores over 52 weeks. Change in UPSIT score from 0 to 8 weeks did not show a significant association with change in the ADAS-Cog or SRT measures over 52 weeks. Conclusion: These negative findings in a relatively large sample of patients with MCI did not replicate results in much smaller samples. Change in odor identification with anticholinergic challenge, and over 8 weeks, may not be useful predictors of cognitive improvement with CheI in patients with MCI. Show more

Keywords: Acetylcholine, Alzheimer’s disease, atropine, mild cognitive impairment, olfaction

DOI: 10.3233/JAD-200021

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 845-854, 2020

Authors: Marmarelis, Vasilis Z. | Shin, Dae C. | Zhang, Rong

Article Type: Research Article

Abstract: Background: Significant reduction of dynamic vasomotor reactivity (DVR) was recently reported in patients with amnestic mild cognitive impairment (MCI) relative to age-matched controls. These results were obtained via a novel approach that utilizes data-based predictive dynamic models to quantify DVR. Objective: Using the same methodological approach, we seek to quantify the dynamic effects of the CO2-driven chemoreflex and baroreflex upon heart-rate in order to examine their possible correlation with the observed DVR impairment in each MCI patient. Methods: The employed approach utilizes time-series data to obtain subject-specific predictive input-output models of the dynamic effects of changes …in arterial blood pressure and end-tidal CO2 (putative “inputs”) upon cerebral blood flow velocity in large cerebral arteries, cortical tissue oxygenation, and heart-rate (putative “outputs”). Results: There was significant dysregulation of CO2-driven heart-rate chemoreflex (p  = 0.0031), but not of baroreflex (p  = 0.5061), in MCI patients relative to age-matched controls. The model-based index of CO2-driven heart-rate chemoreflex gain (CRG) correlated significantly with the DVR index in large cerebral arteries (p  = 0.0146), but not with the DVR index in small/micro-cortical vessels (p  = 0.1066). This suggests that DVR impairment in small/micro-cortical vessels is not mainly due to CO2-driven heart-rate chemoreflex dysregulation, but to other factors (possibly dysfunction of neurovascular coupling). Conclusion: Improved delineation between MCI patients and controls is achieved by combining the DVR index for small/micro-cortical vessels with the CRG index (p  = 2×10–5 ). There is significant correlation (p  < 0.01) between neuropsychological test scores and model-based DVR indices. Combining neuropsychological scores with DVR indices reduces the composite diagnostic index p -value (p ∼10–10 ). Show more

Keywords: cerebral blood flow regulation, cerebrovascular regulation, dynamic vasomotor reactivity, heart-rate chemoreflex modeling, mild cognitive impairment.

DOI: 10.3233/JAD-191238

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 855-870, 2020

Authors: Rodrigo-Herrero, Silvia | Sánchez-Benavides, Gonzalo | Ainz-Gómez, Leire | Luque-Tirado, Andrea | Graciani-Cantisán, Eugenia | Sánchez-Arjona, María Bernal | Maillet, Didier | Jiménez-Hernández, María Dolores | Franco-Macías, Emilio

Article Type: Research Article

Abstract: Background: TMA-93 examines binding by images, a potential advantage for less-educated individuals. Objective: To obtain norms from older Spanish adults for TMA-93. Methods: A cross-sectional normative study was undertaken in a general neurology outpatient clinic of a university hospital in the Southern Spanish region of Andalusia. Partners of patients who attended the clinic were systematically recruited when eligible: aged 50 and over, no memory complaints, and a total score equal or above percentile 10 on Phototest. Age, gender, and educational attainment were considered as sociodemographic variables. TMA-93 was administered and the total score was registered. …Results: The final sample contained 1,131 participants (mean age = 65.7, SD = 9.2), including 305 individuals (27%) who did not completed primary studies. The total score on TMA-93 showed a non-normal, left asymmetric, and leptokurtic distribution (median = 29, interquartile range = 27–30, range = 16–30) mitigated by lower education and older age. Stratified analysis by age and education showed wide variations of the scores for the 5-percentile. Conclusion: TMA-93 runs with a ceiling effect in non-cognitively impaired older Spanish adults. The score for the 5-percentile depends on age and education. The test is feasible for low-educated individuals. Show more

Keywords: Associative memory, cognitive assessment, cross-cultural neuropsychology, memory test

DOI: 10.3233/JAD-191235

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 871-878, 2020

Authors: Espenes, Ragna | Kirsebom, Bjørn-Eivind | Eriksson, Cecilia | Waterloo, Knut | Hessen, Erik | Johnsen, Stein Harald | Selnes, Per | Fladby, Tormod

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) is associated with an increased risk of Alzheimer’s disease (AD). However, patients reporting SCD to their general practitioner are not always referred to a memory clinic. Objective: To investigate whether prior history of medical help-seeking is associated with AD biomarker abnormality, worse cognitive performance, and/or depressive symptoms in SCD. Methods: We compared levels of cerebrospinal fluid (CSF) Aβ 1 - 42 , cognitive performance, and depressive symptoms (15-item Geriatric Depression Scale, GDS-15) between healthy controls (n  = 88), SCD with a history of medical help seeking (SCD-HS, n  = 67), and SCD non help-seekers (SCD-NHS, …n  = 44). Cases with evidence of amyloid plaques (CSF Aβ 1 - 42 ≤708 ng/l) and symptoms of depression (GDS-15≥6) were determined in both SCD groups. Results: The SCD-HS group had lower CSF Aβ 1 - 42 (p  < 0.01), lower word list learning and memory recall (p  < 0.0001), and an increased level of depressive symptoms (p  < 0.0001) compared to controls and SCD-NHS cases. The SCD-HS group had more cases with symptoms of depression (n  = 12, 18%) and amyloid plaques (n  = 18, 27%) compared to SCD-NHS (n  = 1, 2% and n  = 7, 16%, respectively). None of the SCD-HS cases and only one SCD-NHS case had concurrent symptoms of depression and amyloid plaques. The SCD-HS cases showed equal word list learning and memory performance regardless of amyloid status or symptoms of depression. Conclusion: Medical help-seeking in SCD is associated with an increased risk of AD pathology or symptoms of depression. However, subtle memory deficits are seen in SCD help-seekers, also without amyloid plaques or symptoms of depression. Show more

Keywords: Alzheimer’s disease, amyloid plaques, cerebrospinal fluid Aβ1 - 42 , cognitive symptoms, early diagnosis, help-seeking behavior, medical help-seeking, neuropsychiatric symptoms, neuropsychological tests, subjective cognitive decline

DOI: 10.3233/JAD-190712

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 879-890, 2020

Authors: Wimo, Anders | Handels, Ron | Winblad, Bengt | Black, Christopher M. | Johansson, Gunilla | Salomonsson, Stina | Eriksdotter, Maria | Khandker, Rezaul K.

Article Type: Research Article

Abstract: Background: A long-term horizon is necessary when the socioeconomic consequences and the potential effects of interventions in Alzheimer’s disease (AD) are estimated. Objectives: To illustrate the potential societal costs of AD across the disease continuum and to illustrate the potential cost-effectiveness of a hypothetical intervention with disease modifying treatment (DMT). Methods: Based on the Swedish dementia registry, a Markov model was used to simulate a virtual cohort of 100,000 people with mild cognitive impairment (MCI) due to AD (AD-MCI) in Sweden for 40 years starting at the age of 60. A simulated hypothetical intervention assumed a …25% reduction in progression rate during AD-MCI and mild AD-dementia. A comprehensive set of sensitivity analyses was included. Results: The cumulative risk to develop dementia was 96%. The mean simulated survival was 19.0 years. The net present value for a person year with dementia was 252,843 SEK (about 29,500 US$). The cost effectiveness model illustrated how the hypothetical scenario of a 25% reduction in progression to AD-dementia would require 41 AD-MCI patients to be treated to prevent one case of AD-dementia (2,447 avoided AD-dementia cases of 100,000 with AD-MCI). Most scenarios illustrated hypothetical cost effectiveness (based on a willingness to pay level of 600,000 SEK (70,000 US$) per gained QALY), but not cost savings. Discussion: Lifetime societal costs of AD are substantial. A future DMT may be potentially cost-effective given assumed treatment effects and costs, but cost savings are unlikely. Show more

Keywords: Alzheimer’s disease, cost analysis, cost effectiveness, costs, dementia, disease-modifying treatment, economics

DOI: 10.3233/JAD-191055

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 891-902, 2020

Authors: Wroolie, Tonita | Roat-Shumway, Siena | Watson, Katie | Reiman, Eric | Rasgon, Natalie

Article Type: Research Article

Abstract: Background: The apolipoprotein epsilon 4 (APOE4 ) allele is a well-established genetic risk factor for Alzheimer’s disease (AD). However, there are mixed findings as to how the APOE4 allele modifies the effects of both higher low-density lipoprotein cholesterol (LDL) and statin use on cognitive functioning. Objective: This study sought to examine the effects of LDL levels and statin use on verbal learning and memory, as modified by the presence of the APOE4 allele, in a sample of cognitively unimpaired, older adults at risk for AD. Methods: Neuropsychological, LDL, statin use, and APOE4 data …were extracted from an ongoing longitudinal study at the Banner Alzheimer’s Institute in Arizona. Participants were cognitively unimpaired based on Mini-Mental State Examination scores within a normal range, aged 47–75, with a family history of probable AD in at least one first-degree relative. Results: In the whole sample, higher LDL was associated with worse immediate verbal memory in APOE4 non-carriers, but did not have an effect on immediate verbal memory in APOE4 carriers. In APOE4 non-carriers, statin use was associated with better verbal learning, but did not have an effect on verbal learning in APOE4 carriers. Among women, higher LDL in APOE4 carriers was associated with worse verbal learning than in APOE4 non-carriers, and statin use in APOE4 non-carriers was associated with better verbal learning and immediate and delayed verbal memory but worse performances on these tasks in APOE4 carriers. Conclusion: LDL and statin use may have differential effects on verbal learning and/or memory depending on genetic risk for AD. Women appear to be particularly vulnerable to statin use depending on their APOE4 status. Show more

Keywords: APOE4 , at risk for alzheimer’s disease, immediate and delayed verbal memory, LDL cholesterol, statins, verbal learning

DOI: 10.3233/JAD-191090

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 903-910, 2020

Authors: Sahin, Levent | Figueiro, Mariana G.

Article Type: Research Article

Abstract: Background: Coherent 40 Hz (gamma) neural oscillation indicates healthy brain activity and is known to be disrupted in Alzheimer’s disease (AD) patients. 40 Hz entrainment by flickering light is known to significantly attenuate AD pathology in mice. Objective: To demonstrate the feasibility of using a lighting intervention to promote coherent 40 Hz neural oscillation, improved working memory performance, and reduced subjective sleepiness among a population of healthy young adults. If successful, the intervention could be extended to address cognitive impairment associated with mild cognitive impairment and AD. Methods: Nine healthy participants (median age 22 years, five females) were exposed …to one of two lighting conditions per session in a within-subjects counterbalanced manner. The study’s two sessions were separated by 1 week. Custom-built light masks provided either a 40 Hz flickering red light (FRL) intervention or a dark control condition (i.e., total darkness, light mask not energized) at participants’ eyes. Data were collected four times per session: pre-exposure, after 25-min exposure, after 50-min exposure, and post-exposure. Each data collection period included a Karolinska Sleepiness Scale report, an electroencephalogram, and working memory (n -back) auditory performance testing. Results: The FRL intervention induced a significant increase in 40 Hz power and a modest increase in low gamma power. The intervention had no significant impact on working memory performance and subjective sleepiness compared to the control. However, increases in 40 Hz power were significantly correlated with reduced subjective sleepiness. Conclusion: The results clearly demonstrate the feasibility of using a flickering light to increase 40 Hz power. Show more

Keywords: 40 Hz neural oscillation, Alzheimer’s disease, electroencephalography, flickering red light, subjective sleepiness, working memory performance testing

DOI: 10.3233/JAD-200179

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 911-921, 2020

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

Authors: García-García-Patino, Rosalía | Benito-León, Julián | Mitchell, Alex J. | Pastorino-Mellado, Damián | García García, Ricardo | Ladera-Fernández, Valentina | Vicente-Villardón, Jose Luis | Perea-Bartolomé, María Victoria | Cacho, Jesús

Article Type: Research Article

Abstract: Background: Specific cognitive alterations could be one of the predictors that lead to the complex activities of daily living (CADL) impairment in mild cognitive impairment (MCI) and, hence, help to explain the continuum between MCI and dementia. Objective: We aimed to reevaluate the existing uncertainty regarding the impact of memory and executive functions on CADL in patients with MCI. Methods: Caregivers of 161 patients with amnestic multi-domain MCI and of 150 patients with incipient Alzheimer’s disease as well as 100 age-, sex-, and education-matched controls, completed the Interview for Deterioration in Daily Living Activities in Dementia …, a suitable instrument for the description and discrimination of CADL. In addition, all patients and controls were assessed with a neuropsychological battery to measure explicit memory and executive functions performance. Results: Multiple regression analyses showed that in the group of patients with amnestic multi-domain MCI, 67.4% of the variability of the CADL impairment was explained by worse performance on executive functions tests (p  < 0.0001) and 41.8% by different explicit memory components impairment (p  < 0.0001). Further, in patients with incipient AD, 44.0% of the variability of CADL impairment was explained by worse performance on executive functions tests (p  < 0.0001) and 39.9% by different explicit memory components worsening (p  < 0.0001). Conclusions: Memory and executive functions alterations impact similarly on the CADL in both amnestic multi-domain MCI and incipient Alzheimer’s disease. Given the continuum that exists between both conditions, we conclude that CADL impairment may be an important early step in the evolution towards Alzheimer’s disease from amnestic multi-domain MCI. Show more

Keywords: Alzheimer’s disease, amnestic multi-domain MCI, complex activities of daily living, executive functions, memory function

DOI: 10.3233/JAD-191263

Citation: Journal of Alzheimer's Disease, vol. 75, no. 3, pp. 1061-1069, 2020