Journal of Alzheimer's Disease - Volume 71, issue 4

Authors: Linna, Miika | Vuoti, Sauli | Silander, Katariina | Hörhammer, Iiris | Halminen, Olli | Mikkola, Teija | Koivuranta-Vaara, Päivi | Virta, Lauri J. | Koivusalo, Mirkka | Ylisaukko-oja, Tero

Article Type: Research Article

Abstract: Background: The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer’s disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally. Objective: The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD. Methods: This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. …An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals ≥74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model). Results: Early start of anti-dementia medication (treatment started ≤3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication; HR, 0.51; 95% confidence interval (CI), 0.46–0.57). Dementia was the most common recorded cause of death in both groups. Conclusion: This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death. Show more

Keywords: Alzheimer’s disease, cause of death, cholinesterase inhibitors, dementia, Finland, memantine, registry study, risk of death

DOI: 10.3233/JAD-190288

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1297-1308, 2019

Authors: Gyanwali, Bibek | Shaik, Muhammad Amin | Venketasubramanian, Narayanaswamy | Chen, Christopher | Hilal, Saima

Article Type: Research Article

Abstract: Background: Cerebral microbleeds (CMBs) in the lobar and deep locations have been associated with two distinct pathologies namely cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy. However, the role of mixed-location CMBs in cerebrovascular disease and cognitive impairment remain unexplored. Objective: The present study aims to investigate the association of strictly lobar, strictly deep and mixed-location CMBs with cognitive impairment and dementia as well as functional decline. Methods: A prospective case-control study, where 520 patients underwent 3T brain MRI to assess region and lobe-specific CMBs, and other cerebrovascular diseases (CeVD) markers such as cortical infarcts, lacunes, and …white matter hyperintensities. Patients were classified as no cognitive Impairment, cognitive impairment no dementia (CIND), and dementia [Alzheimer’s disease (AD) and vascular dementia (VaD)]. Severity of cognitive impairment was assessed using Clinical Dementia Rating scale. Results: Mixed-location CMBs were associated with dementia [Odds ratio (OR):1.23; 95% confidence interval (CI):1.04, 1.47]. When stratified by the presence of CeVD, mixed-location CMBs were associated with CIND [OR:1.20;95% CI:1.02, 1.42], AD [OR:1.22;95% CI:1.02, 1.46], and VaD [OR:1.33;95% CI:1.08, 1.62]. Furthermore, CMBs in frontal, parietal, and temporal regions were associated with CIND whereas those in parietal, temporal, and occipital regions were associated with AD. Mixed-location CMBs were also associated with increased severity of cognitive impairment [OR:1.02; 95% CI:1.00, 1.05]. Conclusion: Mixed-location CMBs are associated with cognitive impairment and dementia in the presence of CeVD. Furthermore mixed-location CMBs were linked with increased severity of cognitive impairment, suggesting severe parenchymal damage as well as microangiopathy to be common underlying mechanisms in the elderly. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, cerebrovascular disease, cognition, mixed-pathology

DOI: 10.3233/JAD-190540

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1309-1320, 2019

Authors: Gallucci, Maurizio | Pallucca, Claudia | Di Battista, Maria Elena | Fougère, Bertrand | Grossi, Enzo

Article Type: Research Article

Abstract: Background: Nutrition plays an important role in the aging process. Adherence to the Mediterranean diet (MedDiet) has been shown to be associated with lower rates of diseases. Cognitive status seems to be strongly interrelated with physical well-being, so that one influences the other. Physical performance measures are not only associated with clinical and subclinical age-related modifications, but are also able to predict disability, institutionalization, and mortality. Objective: To evaluate prospectively the associations between Mediterranean-Style Dietary Pattern Score (MSDPS), clinical characteristics, and cognition of the population sample of The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. Methods: …Global cognition, physical performance measures, MSDPS, and other clinical features were detected in 2010 in 82 men and 108 women. These characteristics were evaluated in relation to the physical performance measures identified 3.8 years later in 2013 in the same subjects, using a semantic connectivity map, through Auto-CM system, to grasp further and non-linear associations between variables which might remain, otherwise, undetected. Results: The Auto-CM system’s map showed a close association between better levels of global cognition and MSDPS in 2010 and higher physical performance in 2013. On the other hand, worse levels of global cognition and MSDPS in 2010 were associated with lower physical performance in 2013. Conclusion: The prevention models for successful aging may benefit from integrated programs that include cognitive, physical, and dietary interventions, since these aspects are mutually interrelated. Show more

Keywords: Aging, hand grip, mediterranean-style dietary pattern score, mini-mental state examination, physical performance, short physical performance battery, TRELONG

DOI: 10.3233/JAD-190609

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1321-1330, 2019

Authors: Xu, Heng | Yue, Chengjin | Chen, Lin

Article Type: Research Article

Abstract: Many patients with Alzheimer’s disease suffer from severe neuropathic pain. Soluble guanylate cyclase (sGC) is a critical enzyme of the nitric oxide (NO) signaling pathway. Binding of NO to a group of prosthetic heme on sGC initiates the second messenger cGMP synthesis, resulting in increases in the mechanical threshold for neuropathic pain. Nevertheless, the regulation of sGC remains unclear. Here, we aimed to figure out a strategy to reduce sGC levels by microRNA (miRNA) intervention. Bioinformatical studies were then performed to predict sGC-targeting miRNAs; additionally, an assay of dual luciferase reporter was used for evaluating the functional binding of miRNAs …to sGC. Among all sGC-targeting miRNAs, in particularly we found that miR-142-5p markedly inhibited sGC protein translation by pairing to the 3’-UTR of the sGC mRNA. Orthotopic injection of adeno-associated virus carrying miR-142-5p significantly decreased sGC and sGMP levels, resulting in reduction of the neuropathic pain in rats with the left hind leg sciatic nerve injured in the tibia and peroneal branches. In summary, these data show that miR-142-5p induction in injured neurons may be an effective treatment for neuropathic pain and worthy of further investigation as a treatment for those patients with Alzheimer’s disease and neuropathic pain. Show more

Keywords: Alzheimer’s disease, miR-142-5p, neuropathic pain, nitric oxide, soluble guanylate cyclase

DOI: 10.3233/JAD-190743

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1331-1338, 2019

Authors: Frison, Eric | Dufouil, Carole | Helmer, Catherine | Berr, Claudine | Auriacombe, Sophie | Chêne, Geneviève

Article Type: Research Article

Abstract: Diabetes is associated with a higher dementia and mortality risk. However, few studies have accounted for death when estimating the association between diabetes and dementia. We estimated absolute and relative risks of all-cause dementia according to diabetes exposure status in older adults while accounting for competing risk of death using illness-death models. Effect modification by specific characteristics (age, gender, education, cardiovascular risk factors, body mass index, cardiovascular history, depressive symptomatology, impaired renal function, and APOE ɛ 4 genotype) was also investigated. We analyzed the Three-City study data, a French population-based cohort of adults aged 65 years and above who …were followed up for 12 years from 1999–2001. Among 8,328 participants selected in the analytical sample (median age, 73.3 years; 60.3% women), 809 (9.3%) presented with diabetes at baseline. Over a median follow-up period of 8.3 years, 836 participants developed incident dementia. Baseline diabetes was associated with a higher risk of dementia: hazard ratio, 1.79 [95% confidence interval, 1.46–2.19]. No effect modification was shown. Diabetes was associated with a higher 12-year absolute risk of dementia and a lower dementia-free life expectancy (e.g., 14.5% [11.2–18.1] versus 8.7% [7.6–10.2], and 13.4 [12.7–14.1] years versus 16.5 [16.0–17.1] years, respectively, for a 70-year-old woman with the highest level of education). These findings support the potential impact of preventing diabetes on reducing dementia risk in older adults, with a 2-3-year higher dementia-free life expectancy for individuals without diabetes, and inform the design of future interventional trials. Show more

Keywords: Cohort studies, death, dementia, type 2 diabetes mellitus

DOI: 10.3233/JAD-190427

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1339-1350, 2019

Authors: Ralbovsky, Nicole M. | Halámková, Lenka | Wall, Kathryn | Anderson-Hanley, Cay | Lednev, Igor K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and related dementias (ADRDs) are being diagnosed at epidemic rates, with incidence to triple from 35 to 115 million cases worldwide. Most ADRDs are characterized by progressive neurodegeneration, and Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. The ideal moment for diagnosing ADRDs is during the earliest stages of its progression; however, current diagnostic methods are inefficient, expensive, and unsuccessful at making diagnoses during the earliest stages of the disease. Objective: The aim of this project was to utilize Raman hyperspectroscopy in combination with machine learning to develop a …novel method for the diagnosis of AD based on the analysis of saliva. Methods: Raman hyperspectroscopy was used to analyze saliva samples collected from normative, AD, and mild cognitive impairment (MCI) individuals. Genetic Algorithm and Artificial Neural Networks machine learning techniques were applied to the spectral dataset to build a diagnostic algorithm. Results: Internal cross-validation showed 99% accuracy for differentiating the three classes; blind external validation was conducted using an independent dataset to further verify the results, achieving 100% accuracy. Conclusion: Raman hyperspectroscopic analysis of saliva has a remarkable potential for use as a non-invasive, efficient, and accurate method for diagnosing AD. Show more

Keywords: Alzheimer’s disease, artificial neural networks, early diagnosis, genetic algorithm, machine learning, mild cognitive impairment, Raman spectroscopy, saliva

DOI: 10.3233/JAD-190675

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1351-1359, 2019

Authors: Rhea, Elizabeth M. | Nirkhe, Surabhi | Nguyen, Steven | Pemberton, Sarah | Bammler, Theo K. | Beyer, Richard | Niehoff, Michael L. | Morley, John E. | Farr, Susan A. | Banks, William A.

Article Type: Research Article

Abstract: Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer’s disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found …genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement. Show more

Keywords: Alzheimer’s disease, cognition, hippocampus, insulin, intranasal, RNA sequence analysis

DOI: 10.3233/JAD-190707

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1361-1373, 2019

Authors: Fanning, Laura | Ryan-Atwood, Taliesin E. | Bell, J. Simon | Meretoja, Atte | McNamara, Kevin P. | Dārziņš, Pēteris | Wong, Ian C.K. | Ilomäki, Jenni

Article Type: Correction

DOI: 10.3233/JAD-199005

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1375-1378, 2019

Article Type: Correction

DOI: 10.3233/JAD-199006

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1379-1380, 2019

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Benth, Jūratė Šaltytė | Kersten, Hege

Article Type: Correction

DOI: 10.3233/JAD-199007

Citation: Journal of Alzheimer's Disease, vol. 71, no. 4, pp. 1381-1381, 2019