Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

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. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Luikku, Antti J. | Hall, Anette | Nerg, Ossi | Koivisto, Anne M. | Hiltunen, Mikko | Helisalmi, Seppo | Herukka, Sanna-Kaisa | Junkkari, Antti | Sutela, Anna | Kojoukhova, Maria | Korhonen, Ville | Mattila, Jussi | Lötjönen, Jyrki | Rummukainen, Jaana | Alafuzoff, Irina | Jääskeläinen, Juha E. | Remes, Anne M. | Solomon, Alina | Kivipelto, Miia | Soininen, Hilkka | Rauramaa, Tuomas | Leinonen, Ville

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. Objective: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. Methods: 335 shunted iNPH-patients (median 74 years) were followed until death (n  = 185) or 6/2015 (n  = 150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance …of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. Results: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). Conclusion: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD. Show more

Keywords: Alzheimer’s disease, computer-assisted diagnosis, normal pressure hydrocephalus, Data and results has been partly presented as an abstract at Hydrocephalus 2017, Kobe, Japan

DOI: 10.3233/JAD-190334

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Guo, Zongjun | Peng, Xing | Li, Hui-Yun | Wang, Yunlai | Qian, Ying | Wang, Zhihong | Ye, Dongqing | Ji, Xiaoyun | Wang, Zhixin | Wang, Yanjiang | Chen, Dongwan | Lei, Hongxing

Article Type: Research Article

Abstract: Immune dysregulation has been observed in the brain and blood of patients with Alzheimer’s disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these …14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients. Show more

Keywords: Alzheimer’s disease, immune dysregulation, peripheral blood, precision medicine

DOI: 10.3233/JAD-190666

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Ledreux, Aurélie | Hkansson, Krister | Carlsson, Roger | Kidane, Mhretab | Columbo, Laura | Terjestam, Yvonne | Ryan, Eliza | Tusch, Erich | Winblad, Bengt | Daffner, Kirk | Granholm, Ann-Charlotte | Mohammed, Abdul Kadir H.

Article Type: Research Article

Abstract: Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with …an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74  = 4.22, p  = 0.044, partial η 2  = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population. Show more

Keywords: Aging, brain-derived neurotrophic factor, cognitive training, mindfulness, physical exercise

DOI: 10.3233/JAD-190756

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Chanteloup, Gäetan | Cordonnier, Marine | Moreno-Ramos, Teresa | Pytel, Vanesa | Matías-Guiu, Jorge | Gobbo, Jessica | Cabrera-Martín, María Nieves | Gómez-Pinedo, Ulises | Garrido, Carmen | Matías-Guiu, Jordi A

Article Type: Research Article

Abstract: We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Keywords: Alzheimer’s disease, biomarkers, exosomes, frontotemporal dementia, PET

DOI: 10.3233/JAD-190545

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Yokoyama, Shunichi | Yoshinaga, Takuma | Matsuzaki, Juntaro | Suzuki, Hidekazu

Article Type: Research Article

Abstract: Background: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-β increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer’s disease (AD). Objective: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone’s therapeutic ability for AD. Methods: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil +  placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of …the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Results: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6±0.8; teprenone, 0.4±0.8; p  = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, – 1.2±0.5; teprenone, 0.2±0.5; p  = 0.044). Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p  = 0.013) but not with severe atrophy (p  = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Conclusion: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. Trial Registration: UMIN ID: UMIN000016843 Show more

Keywords: Alzheimer’s disease, dementia, donepezil, drug repositioning, geranylgeranylacetone

DOI: 10.3233/JAD-190305

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2019

Authors: Patra, Kalicharan | Giannisis, Andreas | Edlund, Anna K. | Sando, Sigrid Botne | Lauridsen, Camilla | Berge, Guro | Grøntvedt, Gøril Rolfseng | Bråthen, Geir | White, Linda R. | Nielsen, Henrietta M.

Article Type: Research Article

Abstract: The APOE ɛ 4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ɛ 3 conventionally is considered as ‘risk neutral’ although APOE ɛ 3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers, and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers, and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with …either a homozygous APOE ɛ 3 (n  = 31 control subjects, and n  = 14 MCI versus n  = 5 AD patients) or APOE ɛ 4 genotype (n  = 1 control subject, n  = 21 MCI and n  = 7 AD patients). Total plasma apoE levels were lower in APOE ɛ 4-carriers and overall correlated significantly to CSF Aβ42 , p(Thr181)-tau, and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ɛ 3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but unrelated to plasma homocysteine levels. Importantly, the APOE ɛ 3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p  = 0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p  = 0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ɛ 3 subjects. Show more

Keywords: Alzheimer’s disease, apolipoprotein A-II, apolipoprotein E, biomarkers, dementia, dimers

DOI: 10.3233/JAD-190175

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Rudenko, Lauren K. | Wallrabe, Horst | Periasamy, Ammasi | Siller, Karsten H. | Svindrych, Zdenek | Seward, Matthew E. | Best, Merci N. | Bloom, George S.

Article Type: Research Article

Abstract: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not …well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent proteins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amyloid-β, FRET, tauopathies, tau

DOI: 10.3233/JAD-190226

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Lanham, David | Ali, Sana | Davis, Daniel | Rawle, Mark James

Article Type: Research Article

Abstract: Background: Cardiovascular disease remains the most common cause of death in industrialized countries. The use of beta-blockers is well established as a secondary prevention of myocardial infarction. However, little is known about the benefits of beta-blockers for people living with dementia. Objective: To evaluate the use of beta-blockers in people with dementia who have had a myocardial infarction, in order to identify associations between medication use, mortality, re-infarction and functional decline. Methods: We searched for all studies (randomized trials, observational cohorts) reporting beta-blocker use in populations with both dementia and previous myocardial infarction. Relevant keywords were …used in Medline, Embase, and Web of Science up to October 2018. Titles and abstracts were independently screened by two reviewers. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. PRISMA recommendations were followed throughout. Results: Two observational studies were included, representing 10,992 individuals in a community setting and 129,092 individuals from a hospital record-linkage study. One showed use of beta-blockers reduced all-cause mortality (HR 0.74 (95% CI 0.64– 0.86) alongside evidence for an increased rate of functional decline in individuals aged≥65 with moderate to severe cognitive impairment (OR 1.34 (95% CI 1.11– 1.61)). The second study did not find an association between beta-blocker use and mortality in the population living with dementia. Conclusion: There is insufficient evidence to support use of beta-blockers to persons living with dementia. A single study provides limited evidence that beta-blockers improve survival rates but with associated detrimental effects on functional status in nursing home residents with cognitive impairment. Decisions to continue beta-blockers in persons living with dementia should be made on an individual basis. Show more

Keywords: Beta-blockers, dementia, myocardial infarction, secondary prevention, systematic review

DOI: 10.3233/JAD-190503

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Ezzati, Ali | Zammit, Andrea R. | Harvey, Danielle J. | Habeck, Christian | Hall, Charles B. | Lipton, Richard B. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Predicting clinical course of cognitive decline can boost clinical trials’ power and improve our clinical decision-making. Machine learning (ML) algorithms are specifically designed for the purpose of prediction; however. identifying optimal features or algorithms is still a challenge. Objective: To investigate the accuracy of different ML methods and different features to classify cognitively normal (CN) individuals from Alzheimer’s disease (AD) and to predict longitudinal outcome in participants with mild cognitive impairment (MCI). Methods: A total of 1,329 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included: 424 CN, 656 MCI, and 249 AD individuals. …Four feature-sets at baseline (hippocampal volume and volume of 47 cortical and subcortical regions with and without demographics and APOE4 ) and six machine learning methods (decision trees, support vector machines, K-nearest neighbor, ensemble linear discriminant, boosted trees, and random forests) were used to classify participants with normal cognition from participants with AD. Subsequently the model with best classification performance was used for predicting clinical outcome of MCI participants. Results: Ensemble linear discriminant models using demographics and all volumetric magnetic resonance imaging measures as feature-set showed the best performance in classification of CN versus AD participants (accuracy = 92.8%, sensitivity = 95.8%, and specificity = 88.3%). Prediction accuracy of future conversion from MCI to AD for this ensemble linear discriminant at 6, 12, 24, 36, and 48 months was 63.8% (sensitivity = 74.4, specificity = 63.1), 68.9% (sensitivity = 75.9, specificity = 67.8), 74.9% (sensitivity = 71.5, specificity = 76.3), 75.3%, (sensitivity = 65.2, specificity = 79.7), and 77.0% (sensitivity = 59.6, specificity = 86.1), respectively. Conclusions: Machine learning models trained for classification of CN versus AD can improve our prediction ability of MCI conversion to AD. Show more

Keywords: Alzheimer’s disease, classification, early diagnosis, machine learning, magnetic resonance imaging, mild cognitive impairment, predictive analytics

DOI: 10.3233/JAD-190262

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019