Pages 671-688
Review
Morena Zusso, Massimo Barbierato, Laura Facci, Stephen D. Skaper, Pietro Giusti
Neuroepigenetics and Alzheimer’s Disease: An Update
Abstract: Epigenetics is the study of changes in gene expression which may be triggered by both genetic and environmental factors, and independent from changes to the underlying DNA sequence—a change in phenotype without a change in genotype—which in turn affects how cells read genes. Epigenetic changes represent a regular and natural occurrence but can be influenced also by factors such as age, environment, and disease state. Epigenetic modifications can manifest themselves not only as the manner in which cells terminally differentiate, but can have also deleterious effects, resulting in diseases such as cancer. At least three systems including DNA methylation, histone modification, and non-coding RNA (ncRNA)-associated gene silencing are thought to initiate and sustain epigenetic change. For example, in Alzheimer’s disease (AD), both genetic and non-genetic factors contribute to disease etiopathology. While over 250 gene mutations have been related to familial AD, less than 5% of AD cases are explained by known disease genes. More than likely non-genetic factors, probably triggered by environmental factors, are causative factors of late-onset AD. AD is associated with dysregulation of DNA methylation, histone modifications, and ncRNAs. Among the classes of ncRNA, microRNAs (miRNAs) have a well-established regulatory relevance. MicroRNAs are highly expressed in CNS neurons, where they play a major role in neuron differentiation, synaptogenesis, and plasticity. MicroRNAs impact higher cognitive functions, as their functional impairment is involved in the etiology of neurological diseases, including AD. Alterations in the miRNA network contribute to AD disease processes, e.g., in the regulation of amyloid peptides, tau, lipid metabolism, and neuroinflammation. MicroRNAs, both as biomarkers for AD and therapeutic targets, are in the early stages of exploration. In addition, emerging data suggest that altered transcription of long ncRNAs, endogenous, ncRNAs longer than 200 nucleotides, may be involved in an elevated risk for AD.
Pages 689-707
Stephen P. Salloway*, Reisa Sperling*, Nick C. Fox, Marwan N. Sabbagh, Lawrence S. Honig, Anton P. Porsteinsson, Hany Rofael, Nzeera Ketter, Daniel Wang, Enchi Liu, Stephen Carr, Ronald S. Black, H. Robert Brashear (Handling Associate Editor: Katherine Bangen) *These authors contributed equally to this work.
Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer’s Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study
Abstract: Background: A 3-year extension of two Phase III parent studies of intravenous (IV) bapineuzumab in patients with mild-to-moderate Alzheimer’s disease dementia (apolipoprotein (APOE) ε4 carriers and noncarriers) is summarized. Objectives: The primary and secondary objectives were to evaluate the long-term safety, tolerability, and maintenance of efficacy of bapineuzumab. Methods: A multicenter study in patients who had participated in double-blind placebo-controlled parent studies. Patients enrolled in the extension study were assigned to receive IV infusions of bapineuzumab (0.5 or 1.0 mg/kg) every 13 weeks until termination but were blinded to whether they had received bapineuzumab or placebo in the parent studies. Results: A total of 1,462 (688 were APOE ε4 carriers and 774 were noncarriers) patients were enrolled. Extension-onset adverse events occurred in >81% of the patients in each dose group. Fall, urinary tract infection, agitation, and ARIA-E occurred in ≥10% of participants. The incidence proportion of ARIA-E was higher among carriers and noncarriers who received bapineuzumab for the first time in the extension study (11.8% and 5.4%, respectively) versus those who were previously exposed in the parent studies (5.1% and 1.3%, respectively). After 6 to 12 months exposure to bapineuzumab IV in the extension study, similar deterioration of cognition and function occurred with no significant differences between the dose groups. Conclusions: Infusion of bapineuzumab 0.5 or 1.0 mg/kg every 13 weeks for up to 3 years was generally well tolerated, with a safety and tolerability profile similar to that in previous studies.
Pages 709-722
Wen Hu, Yunn Chyn Tung, Yanchong Zhang, Fei Liu, Khalid Iqbal
Involvement of Activation of Asparaginyl Endopeptidase in Tau Hyperphosphorylation in Repetitive Mild Traumatic Brain Injury
Abstract: Traumatic brain injury (TBI) is an established risk factor for the development of neurodegeneration and dementia late in life. Repetitive mild TBI (r-mTBI) is directly associated with chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder characterized by focal perivascular to widespread Alzheimer-type neurofibrillary pathology of hyperphosphorylated tau. Studies in animal models have shown hyperphosphorylation of tau after TBI. However, the molecular mechanisms by which TBI leads to tau pathology are not understood. In this study, we employed western blots and immunohistochemistry to test, in triple-transgenic mouse model of Alzheimer’s disease (3xTg-AD), the effect of r-mTBI on tau hyperphosphorylation and activation of asparaginylendopeptidase (AEP), a cysteine proteinase which is known to be involved in tau hyperphosphorylation. We found that the level of active AEP was increased and correlated with the level of tau hyperphosphorylation following r-mTBI, and that fimbria showed increased immunoreactivity to phospho-tau. In addition, inhibitor 2 of protein phosphatase 2A (I2PP2A) was translocated from neuronal nucleus to the cytoplasm and colocalized with hyperphosphorylated tau. These data suggest the involvement of AEP-I2PP2A-PP2A-ptau pathway in tau pathology in TBI.
Pages 723-734
Jes Buster Madsen*, Jonas Folke*, Bente Pakkenberg (Handling Associate Editor: Emilio Artacho-Pérula) *These authors contributed equally to this work.
Stereological Quantification of Plaques and Tangles in Neocortex from Alzheimer’s Disease Patients
Abstract: We estimated by stereological methods the neocortical volume occupied by plaques and tangles in females dying with severe Alzheimer’s disease (AD), age-matched female subjects with severe vascular dementia, and normal control brains. Stereological investigations include a uniform sampling of the tissue in the whole of neocortex and its subdivisions. Resultant volume estimates provide information about the overall burden of these two pathological changes and their volume fractions and allow for correlational studies between the pathological changes and factors such as the total neocortical neuronal cell numbers, dementia test scores, and age. We estimated the volume of plaques and tangles in entire neocortex and frontal-, temporal-, parietal-, and occipital cortex in nine female AD brains, four female patients dying with vascular dementia, and six neurologically normal female control brains using point-counting in uniform samples of neocortex. The volume occupied by plaques comprised approximately 1% of neocortex, while the neocortical tangles made up approximately 0.01% of neocortex of AD patients but were scarcely present in the other study groups. The individual tangle and plaque volumes did not correlate to the ultimate dementia score of the AD subjects, despite correlating with reduced neocortical volume. In neocortex of AD patients, the burden of plaques and tangles is much higher than that in patients with severe vascular dementia or normal older women but only occupy a small fraction of the neocortical volume.
Pages 735-749
Jana Lehmann, Bernhard Michalowsky, Anika Kaczinski, René Thyrian, Nele Schenk, Alexander Esser, Ina Zwingmann, Wolfgang Hoffmann
The Impact of Hospitalization on Readmission, Institutionalization, and Mortality of People with Dementia: A Systematic Review and Meta-Analysis
Abstract: Background: People with dementia (PwD) are at a high risk of hospitalization. Hospitals are often not adequately equipped for PwD and discharges often come unexpected. Therefore, PwD are at a risk of adverse outcomes. However, information about those outcomes is rare but crucial for the development of preventive strategies. Objectives: To conduct a quantitative systematic review and meta-analyses on the impact of a hospitalization on readmission, institutionalization, and mortality in PwD. To identify factors associated with these outcomes. Methods: PubMed, CENTRAL, and ScienceDirect were searched for studies including terms for dementia, hospital, readmission, institutionalization, and mortality. Relevant studies assessed by a quality criteria sheet. Results were summarized in a table. Meta-analysis was conducted with Review Manager 5.3. Results: The search yielded 1,108 studies; 20 fulfilled the inclusion criteria and 10 studies were eligible for meta-analyses. The incidence and relative risk (RR) of mortality (RR 1.74 CI95% 1.50, 2.05) and institutionalization (RR: 2.16 CI95% 1.31, 3.56) of PwD was significantly higher as compared to people without dementia. Results according to readmission rate were inconsistent. Factors significantly associated with the examined adverse outcomes were severity of dementia, number of medications and deficits in daily living activities. Conclusion: Hospitalization of PwD lead to adverse outcomes. An improvement in the identification of and care for PwD in the acute setting as well as in after care in the community setting, especially in the interface between both settings, is required to prevent adverse outcomes in hospitalized PwD.
Pages 751-760
Ales Bartos, Lenka Fialová, Jana Švarcová
Lower Serum Antibodies Against Tau Protein and Heavy Neurofilament in Alzheimer’s Disease
Abstract: Background: Unlike antibodies against amyloid-β, little is known about serum antibodies to neuron-specific cytoskeletal proteins in patients with Alzheimer´s disease (AD). Objective: We aimed to study IgG autoantibodies against tau protein, light (NFL) and heavy subunits (NFH) of neurofilaments in serum of AD patients and elderly controls and to explore the evolution of antineurocytoskeletal antibody levels over time. Methods: Antibodies against three targets (tau, NFL, and NFH) were measured using ELISA in 100 serum samples from 51 cognitively normal elderly controls and 49 patients with AD. Our primary cross-sectional design was further extended to monitor fluctuations over 1-2 years in a subset of individuals. Results: The AD patients had lower levels of anti-tau antibodies (p = 0.03) and even lower anti-NFH antibodies (p = 0.005) than those in the control group at baseline. On the contrary, anti-NFL antibodies or total IgG concentrations in serum did not differ. All three antibodies remained stable in both groups except for a selective and significant anti-tau decline in AD patients (p = 0.03). Conclusions: The different responses to these antigens suggest some antibody selectivity in AD. The significant decline was observed for only serum anti-tau antibodies in AD patients over time and it corresponds to lower anti-tau levels in these patients. Our findings indicate a special feature of disease-relevant antigens and humoral autoimmunity in AD.
Pages 761-774
Lasse M. Giil, Dag Aarsland, Kristoffer Hellton, Anders Lund, Harald Heidecke, Kai Schulze-Forster, Gabriela Riemekasten, Audun Osland Vik-Mo, Einar K. Kristoffersen, Christian A. Vedeler, Jan Erik Nordrehaug
Antibodies to Multiple Receptors are Associated with Neuropsychiatric Symptoms and Mortality in Alzheimer’s Disease: A Longitudinal Study
Abstract: Background: Endogenous antibodies to signaling molecules and receptors (Abs) are associated with Alzheimer’s disease (AD). Objectives: To investigate the association of 33 Abs to dopaminergic, serotoninergic, muscarinic, adrenergic, vascular, and immune receptors with cognitive, neuropsychiatric, and mortality outcomes. Methods: Ninety-one patients with mild AD were followed annually for 5 years with the Mini-Mental State Examination (MMSE) and the Neuropsychiatric Inventory (NPI; composite outcomes: “psychosis” (item 1 + 2), “mood” (item 4 + 5 + 7), and “agitation” (item 3 + 8 + 9)). Abs were quantified in sera obtained at baseline by ELISA and reduced to principal components (PCs). Associations between Abs and outcomes were assessed by a mixed model (MMSE decline), zero-inflated fixed effects count models (composite NPI scores), and Cox regression (mortality). The resulting p-values were adjusted for multiple testing according to a false discovery rate of 0.05 (Benjamini-Hochberg). Results: The measured levels of the 33 Abs formed four PCs. PC1 (dopaminergic and serotonergic Abs) was associated with increased mortality (Hazard ratio 2.57, p < 0.001), PC2 (serotonergic, immune, and vascular Abs) with decreased agitation symptoms (β -0.19, p < 0.001), and PC3 (cholinergic receptor Abs) with increased mood symptoms (β 0.04, p = 0.002), over time. There were no associations between Abs and MMSE decline. Conclusion: The associations between Abs, mortality, and neuropsychiatric symptoms reported in this cohort are intriguing. They cannot, however, be generalized. Validation in independent sample sets is required.
Pages 775-785
Niamh A. O’Regan, James Fitzgerald, Dimitrios Adamis, David William Molloy, David Meagher, Suzanne Timmons (Handling Associate Editor: Manuel Montero-Odasso)
Predictors of Delirium Development in Older Medical Inpatients: Readily Identifiable Factors at Admission
Abstract: Background: Identifying patients at high risk of delirium is crucial to facilitate prevention. Although dementia is the most consistent risk factor across populations, it remains under-diagnosed. Hence understanding other markers of delirium vulnerability on admission is important. Objective: We aimed to identify predictors of incident delirium development in older medical inpatients that were readily identifiable at presentation to the emergency department. Methods: Medical inpatients of ≥70 years were assessed on admission for delirium using the Revised Delirium Rating Scale (DRS-R98) and those with prevalent delirium were excluded. Consenting non-delirious patients were then assessed daily using the DRS-R98. Data pertaining to multiple baseline delirium risk factors were collected, including pre-morbid dementia. Multivariable logistic regression was used to examine which factors predicted the development of incident delirium. Results: Of 555 patients approached, 184 (33.1%) had prevalent delirium. Following other exclusions, 191 were included in the study and 61 developed incident delirium. Predictors of incident delirium on multivariable analysis, controlling for confounders, were dementia (OR 2.54, 95% CI 1.01-6.43, p=0.048); Barthel Index score (OR 1.15 for each unit decrease in score, 95% CI 1.06-1.25, p=0.001), and Modified Cumulative Illness Rating Scale score (OR 1.13 for each unit increase in score, 95% CI 1.05-1.22, p= 0.001). Conclusion: Dementia is a well-known risk factor for delirium; however, it too is under-recognized and on admission can be missed. Conversely, the Barthel Index is a simple and widely used measure of functional ability that may prove useful in stratifying those at risk of in-hospital delirium on admission.
Pages 787-800
Ioanna Chalatsa*, Demetrios A. Arvanitis*, Eleni V. Mikropoulou, Athina Giagini, Zeta Papadopoulou-Daifoti, Nektarios Aligiannis, Maria Halabalaki, Anthony Tsarbopoulos, Leandros A. Skaltsounis, Despina Sanoudou (Handling Associate Editor: Antonios Politis) *These authors contributed equally to this work.
Beneficial Effects of Sideritis scardica and Cichorium spinosum against Amyloidogenic Pathway and Tau Misprocessing in Alzheimer’s Disease Neuronal Cell Culture Models
Abstract: Background: Natural products are a significantly underutilized source of potential treatments against human disease. Alzheimer’s disease (AD) is a prime example of conditions that could be amenable to such treatments as suggested by recent findings. Objective: Aiming to identify novel potentially therapeutic approaches against AD, we assessed the effects of Cichorium spinosum and Sideritis scardica extracts, both distinct components of the Mediterranean diet. Methods/Results: After the detailed characterization of the extracts’ composition using LC-HRMS methods, they were evaluated on two AD neuronal cell culture models, namely the AβPP overexpressing SH-SY5Y-AβPP and the hyperphosphorylated tau expressing PC12-htau. Initially their effect on cell viability of SH-SY5Y and PC12 cells was examined, and subsequently their downstream effects on AβPP and tau processing pathways were investigated in the SH-SY5Y-AβPP and PC12-htau cells. We found that the S. scardica and C. spinosum extracts have similar effects on tau, as they both significantly decrease total tau, the activation of the GSK3β, ERK1 and/or ERK2 kinases of tau, as well as tau hyperphosphorylation. Furthermore, both extracts appear to promote AβPP processing through the alpha, non-amyloidogenic pathway, albeit through partly different mechanisms. Conclusions: These findings suggest that C. spinosum and S. scardica could have a notable potential in the prevention and/or treatment of AD, and merit further investigations at the in vivo level.
Pages 801-813
Stefan J. Teipel, Coraline Metzger, Frederic Brosseron, Katharina Buerger, Katharina Brueggen, Cihan Catak, Dominik Diesing, Laura Dobisch, Klaus Fließbach, Christiana Franke, Michael Heneka, Ingo Kilimann, Barbara Kofler, Felix Menne, Oliver Peters, Alexandra Polcher, Josef Priller, Anja Schneider, Annika Spottke, Eike J. Spruth, Manuela Thelen, René J. Thyrian, Michael Wagner, Emrah Düzel, Frank Jessen, Martin Dyrba, and the DELCODE study group
Multicenter Resting State Functional Connectivity in Prodromal and Dementia Stages of Alzheimer’s Disease
Abstract: Background: Alterations of intrinsic networks from resting state fMRI (rs-fMRI) have been suggested as functional biomarkers of Alzheimer’s disease (AD). Objective: To determine the diagnostic accuracy of multicenter rs-fMRI for prodromal and preclinical stages of AD. Methods: We determined rs-fMRI functional connectivity based on Pearson’s correlation coefficients and amplitude of low-frequency fluctuation in people with subjective cognitive decline, people with mild cognitive impairment, and people with AD dementia compared with healthy controls. We used data of 247 participants of the prospective DELCODE study, a longitudinal multicenter observational study, imposing a unified fMRI acquisition protocol across sites. We determined cross-validated discrimination accuracy based on penalized logistic regression to account for multicollinearity of predictors. Results: Resting state functional connectivity reached significant cross-validated group discrimination only for the comparison of AD dementia cases with healthy controls, but not for the other diagnostic groups. AD dementia cases showed alterations in a large range of intrinsic resting state networks, including the default mode and salience networks, but also executive and language networks. When groups were stratified according to their CSF amyloid status that was available in a subset of cases, diagnostic accuracy was increased for amyloid positive mild cognitive impairment cases compared with amyloid negative controls, but still inferior to the accuracy of hippocampus volume. Conclusion: Even when following a strictly harmonized data acquisition protocol and rigorous scan quality control, widely used connectivity measures of multicenter rs-fMRI do not reach levels of diagnostic accuracy sufficient for a useful biomarker in prodromal stages of AD.
Pages 815-826
Hanna Lu, Ni Xi, Ada W. T. Fung, Linda C. W. Lam
Mapping the Proxies of Memory and Learning Function in Senior Adults with High-performing, Normal Aging and Neurocognitive Disorders
Abstract: Background: Memory and learning, as the core brain function, shows controversial results across studies focusing on aging and dementia. One of the reasons is because of the multi-faceted nature of memory and learning. However, there is still a dearth of comparable proxies with psychometric and morphometric portrait in clinical and non-clinical populations. Objective: We aim to investigate the proxies of memory and learning function with direct and derived measures and examine their associations with morphometric features in senior adults with different cognitive status. Methods: Based on two modality-driven tests, we assessed the component-specific memory and learning in the individuals with high performing (HP), normal aging, and neurocognitive disorders (NCD) (n = 488). Structural magnetic resonance imaging was used to measure the regional cortical thickness with surface-based morphometry analysis in a subsample (n=52). Results: Compared with HP elderly, the ones with normal aging and minor NCD showed declined recognition memory and working memory, whereas had better learning performance (derived scores). Meanwhile, major NCD patients showed more breakdowns of memory and learning function. The correlation between proxies of memory and learning and cortical thickness exhibited the overlapped and unique neural underpinnings. Conclusions: The proxies of memory and learning could be characterized by component-specific constructs with psychometric and morphometric bases. Overall, the constructs of memory are more likely related to the pathological changes, and the constructs of learning tend to reflect the cognitive abilities of compensation.
Pages 827-833
Jens Bohlken, Louis Jacob, Hendrik van den Bussche, Karel Kostev
The Influence of Polypharmacy on the Initiation of Anti-Dementia Therapy in Germany
Abstract: The goal of the present retrospective study was to focus on the potential influence of polypharmacy on the initiation of antidementia therapy in patients diagnosed with dementia in general practices in Germany. The current study sample included patients diagnosed with dementia in 1,217 general practices in Germany between 2014 and 2016 (index date). The primary outcome measure was the rate of prescription of anti-dementia drugs within one year following the index date. The explanatory variable was the number of different drugs prescribed at baseline per patient. Independent variables included age, sex, and type of dementia. Logistic regression analyses were conducted to study the impact of the number of different drugs prescribed at baseline per participant on the odds of receiving anti-dementia therapy (in all patients and in patients diagnosed with Alzheimer’s disease). The study included 21,888 patients with all-cause-dementia. Mean age was 80.2 years (SD=7.3 years) and 61.4% of the study population were women. Individuals receiving six drugs or more at baseline were significantly less likely to be prescribed anti-dementia treatment when compared to those without any drug at baseline (6-9 drugs: odds ratio [OR]=0.75; ≥10 drugs: OR=0.58). In the subgroup of patients with Alzheimer’s disease, the odds of being prescribed anti-dementia therapy were lower in individuals with four drugs or more, compared to patients who had not been prescribed any drugs at baseline (4-5 drugs: OR=0.60; 6-9 drugs: OR=0.49; ≥10 drugs: OR=0.36). There is a negative association between polypharmacy and antidementia therapy initiation in general practices in Germany.
Pages 835-857
Craig P. Hutton, Jennifer A. Lemon, Boris Sakic, C. David Rollo, Douglas R. Boreham, Margaret Fahnestock, J. Martin Wojtowicz, Suzanna Becker (Handling Associate Editor: Isabelle Aubert)
Early Intervention with a Multi-Ingredient Dietary Supplement Improves Mood and Spatial Memory in a Triple Transgenic Mouse Model of Alzheimer’s Disease
Abstract: The increasing global burden of Alzheimer’s disease (AD) and failure of conventional treatments to stop neurodegeneration necessitates an alternative approach. Evidence of inflammation, mitochondrial dysfunction, and oxidative stress prior to the accumulation of amyloid-β in the prodromal stage of AD (mild cognitive impairment; MCI) suggests that early interventions which counteract these features, such as dietary supplements, may ameliorate the onset of MCI-like behavioral symptoms. We administered a polyphenol-containing multiple ingredient dietary supplement (MDS), or vehicle, to both sexes of triple transgenic (3xTg-AD) mice and wildtype mice for 2 months from 2-4 months of age. We hypothesized that the MDS would preserve spatial learning, which is known to be impaired in untreated 3xTg-AD mice by 4 months of age. Behavioral phenotyping of animals was done at 1-2 and 3-4 months of age using a comprehensive battery of tests. As previously reported in males, both sexes of 3xTg-AD mice exhibited increased anxiety-like behavior at 1-2 months of age, prior to deficits in learning and memory, which did not appear until 3-4 months of age. The MDS did not reduce this anxiety or prevent impairments in novel object recognition (both sexes) or on the water maze probe trial (females only). Strikingly, the MDS specifically prevented 3xTg-AD mice (both sexes) from developing impairments (exhibited by untreated 3xTg-AD controls) in working memory and spatial learning. The MDS also increased sucrose preference, an indicator of hedonic tone. These data show that the MDS can prevent some, but not all, psychopathology in an AD model.
Pages 859-873
Elena Schartmann, Sarah Schemmert, Nicole Niemietz, Dominik Honold, Tamar Ziehm, Markus Tusche, Anne Elfgen, Ian Gering, Oleksandr Brener, Nadim Joni Shah, Karl-Josef Langen, Janine Kutzsche, Dieter Willbold, Antje Willuweit
In Vitro Potency and Preclinical Pharmacokinetic Comparison of All D Enantiomeric Peptides Developed for the Treatment of Alzheimer’s Disease
Abstract: Diffusible amyloid β (Aβ) oligomers are currently presumed to be the most cytotoxic Aβ assembly and held responsible to trigger the pathogenesis of Alzheimer’s disease (AD). Thus, Aβ oligomers are a prominent target in AD drug development. Previously, we reported on our solely D enantiomeric peptide D3 and its derivatives as AD drug candidates. Here, we compare one of the most promising D3 derivatives, ANK6, with its tandem version (tANK6), and its head-to-tail cyclized isoform (cANK6r). In vitro tests investigating the D peptides’ potencies to inhibit Aβ aggregation, eliminate Aβ oligomers, and reduce Aβ-induced cytotoxicity revealed that all three D peptides efficiently target Aβ. Subsequent preclinical pharmacokinetic studies of the three all-D peptides in wildtype mice showed promising blood-brain barrier permeability with cANK6r yielding the highest levels in brain. The peptides’ potencies to lower Aβ toxicity and their remarkable brain/plasma ratios make them promising AD drug candidates.
Pages 875-887
Olivier Beauchet, Harmehr Sekhon, John Barden, Teresa Liu-Ambrose, Victoria L. Chester, Tony Szturm, Sébastien Grenier, Guillaume Léonard, Louis Bherer, Gilles Allali, Canadian Gait Consortium
Association of Motoric Cognitive Risk Syndrome with Cardiovascular Disease and Risk Factors: Results from an Original Study and Meta-Analysis
Abstract: Background: Motoric cognitive risk (MCR) syndrome, a recently described pre-dementia syndrome, has been associated with cardiovascular disease and their risk factors (CVDRF). Objective: To determine whether MCR syndrome was associated with CVDRF in French community-dwelling older adults, and to quantitatively evaluate, with a systematic review and meta-analysis, the association of MCR syndrome with CVDRF. Methods: Based on a cross-sectional design, 238 older adults without dementia were selected from the French GAIT study. An English and French systematic Medline and Embase search (without limiting date of publication) was also conducted in February 2017 using the terms “motoric cognitive risk syndrome” OR “motoric cognitive risk” OR “motoric risk”. The systematic review and meta-analysis included 8 studies. CVDRF were defined as cardiovascular diseases, hypertension, diabetes, stroke, obesity and abnormal waist-hip ratio (WHR). Results: The prevalence of MCR syndrome in the current original study was 16.8%. MCR syndrome was associated with abnormal WHR (Odds ratio [OR] >2.8 with p < 0.020) and high blood pressure (OR >2.5 with p < 0.025). Of the 202 originally identified abstracts, 7 (3.5%) were selected for the systematic review. The meta-analysis showed that all pooled OR were significant with a p-value < 0.001 (OR = 1.41 for cardiovascular diseases, 1.21 for hypertension, 1.44 for diabetes, 2.05 for stroke, and 1.34 for obesity). When pooling all CVDRF, the overall OR was 1.38 (95% CI, 1.33-1.45) with p-value < 0.001. Conclusion: MCR syndrome is significantly associated with CVDRF. These findings suggest that a vascular mechanism may underlie the pathophysiology of MCR syndrome.
Pages 889-897
Claire Paquet, Elodie Bouaziz-Amar, Emmanuel Cognat, Lisette Volpe-Gillot, Victor Haddad, Florence Mahieux, Siham Dekimeche, Benedicte Desfontaines, Hugues Chabriat, Catherine Belin, Antonio Texeira, Stephane Goutagny, Frank Questel, Julien Azuar, Pierre-Olivier Sellier, Jean-Louis Laplanche, Jacques Hugon, Julien Dumurgier
Distribution of Cerebrospinal Fluid Biomarker Profiles in Patients Explored for Cognitive Disorders
Abstract: Background: CSF Alzheimer’s disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies. Objective: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders. Methods: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults. Results 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N- profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations. Conclusions: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N- patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population.
Pages 899-910
Craig W. Ritchie, Rezaul K. Khandker, James Pike, Christopher M. Black, Eddie Jones, Baishali M. Ambegaonkar
Real World, Multinational, Retrospective Observational Survey of the ADAS-Cog and Associations with Healthcare Resource Utilization in Patients with Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer’s Disease Assessment Scale-Cognition subscale (ADAS Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. Objective: This study evaluated the relationship between ADAS Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU) measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. Methods: A retrospective observational survey of physicians and their consulting patients with multiple ADAS Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS Cog rate of change, baseline ADAS Cog, and their interaction included as exposure variables. Results: 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p<0.05; joint test) with increasing ADAS Cog scores (indexing clinical deterioration). Conclusion: The results suggest that further understanding the relationship between HCRU and ADAS Cog changes in real-world clinical practice could potentially provide a baseline upon which the success of disease modifying, as well as newer symptomatic, dementia therapies can be judged.
Pages 911-923
Yuanxin Chen, Patrick Lim, Kem A. Rogers, Brian K. Rutt, John A. Ronald
In Vivo MRI of Amyloid Plaques in a Cholesterol-Fed Rabbit Model of Alzheimer’s Disease
Abstract: Hypercholesterolemia has been identified as risk factors for Alzheimer's disease. In this study, rabbits were fed either a cholesterol diet or normal chow diet for 24 months. At endpoint, in vivo MRI was performed at the field strength of 3 Tesla using fast imaging employing steady state acquisition without (FIESTA) or with susceptibility-weighted post-processing (SWI-FIESTA) and susceptibility-weighted imaging with multi-echo acquisition (SWAN). This imaging revealed signal voids/hypointensities throughout the cortex, sub-cortex, and hippocampus of cholesterol-fed animals compared to control animals. Quantitative image analysis corroborated these qualitative findings and highlighted that SWI processing of FIESTA images significantly improved the detectability of plaques (p<0.05). Aβ immunostaining and Prussian blue staining for iron demonstrated that the voids in MR images corresponded to iron-laden Aβ-positive plaques. This study demonstrates non-invasive in vivo visualization of Aβ plaques in a diet-induced large animal model of Alzheimer’s disease. This work lays the foundation for future work focusing on longitudinal monitoring of plaque formation in this model and the effects of diet or drug interventions.
Pages 925-932
Urs Strohmaier, Felix Keller, Ingo Kilimann, Bernhard Michalowsky, Diana Wucherer, Ina Zwingmann, Stefan Teipel, Wolfgang Hoffmann, Jochen René Thyrian
Patients with Dementia in Primary Care: Who Is Referred to a Neurologist/Psychiatrist and What Patient-Oriented Factors Are Associated with the Visit?
Abstract: Background: The current guidelines imply that basic medical diagnostics for dementia should be provided by general practitioners in cooperation with other specialists such as neurologists and psychiatrists. Objectives: The aims of this paper were to 1) compare the dementia patients of general practice residents whose care is co-managed by neurology/psychiatry residents with those whose care is not; 2) identify the patient variables associated with the utilization of neurological and psychiatric specialists; and 3) describe the frequency of imaging use a for dementia patients in primary care. Methods: The analyses utilized data from 485 individuals who screened positive for dementia in primary care (PWD). Clinical variables and the utilization of specialists were assessed via medical records and face-to-face interviews. The factors associated with the utilization of specialists were assessed using multivariate linear regression and included age, sex, relationship status, cognitive impairment, depression, activities of daily living, and formal diagnosis of dementia. Results: Our results show that 89 out of 485 study participants (18.4%) were referred to specialists 12 months prior to assessment. Of these 89 individuals, 14.6% (n=13) did not receive imaging diagnostics, while 39.3% (n=35) received brain imaging by CT scan and 46.1% (n=41) by MRI. PWD referred to specialists differed from those not referred, in age, relationship status, and the presence of a formal diagnosis. Our multivariate analysis revealed that younger age (OR=0.95; 95%-confidence interval 0.90-0.99; p=0.04) and higher functional impairment (OR=1.15; 95%-confidence interval 1.02-1.30; p=0.02) were associated with a visit to a specialist. Discussion: Only 1 out of every 4 to 5 individuals who have screened positive for dementia have visited a specialist in psychiatry or neurology. While in general, women utilized specialists less often than men, younger and more functionally impaired patients were more likely to be sent to a specialist by their treating general practitioner. Almost 90% of the patients sent to a specialist received cranial neuroimaging, suggesting high adherence to diagnostic guidelines in specialized care.
Pages 933-941
Sandra Garrido, Catherine J Stevens, Esther Chang, Laura Dunne, Janette Perz (Handling Associate Editor: Amy Clements-Cortes)
Music and Dementia: Individual Differences in Response to Personalized Playlists
Abstract: Personalized music playlists are increasingly being used in health-care contexts to address the psychological and behavioral symptoms in people with dementia. However, there is little understanding of how people with different mental health histories and symptoms respond differently to music. A factorial experiment was conducted to investigate the influence of depression, anxiety, apathy, and cognitive decline on affective response to music. Ninety-nine people with dementia listened to three music playlists based on personal preferences. Activation of facial action units and behavioral observation were measured continuously. Results demonstrated that people with high levels of depression and with symptoms of Alzheimer’s type dementia demonstrated increased levels of sadness when listening to music. People with low depression but high levels of apathy demonstrated the highest behavioral evidence of pleasure during music listening, although behavioral evidence declined with severity of cognitive decline. It is concluded that as well as accounting for personal preferences, music interventions for people with dementia need to take mental health history and symptoms into account.
Pages 943-955
Bingyu Li, Pengli Xu, Shuyan Wu, Zhixian Jiang, Zhijian Huang, Qian Li, Danhong Chen
Diosgenin Attenuates Lipopolysaccharide-Induced Parkinson’s Disease by Inhibiting the TLR/NF-κB Pathway
Abstract: Background: Parkinson’s disease (PD) is a neurodegenerative disease characterized by loss of dopaminergic neurons in the substantia nigra. Diosgenin is a natural steroid saponin which was shown to play a beneficial role in Alzheimer’s disease. Objective: This study sought to investigate the potential effect of diosgenin on a rat model of PD. Methods: Sprague Dawley rats were subjected to intra-striatal injection of lipopolysaccharide (LPS) and treated with diosgenin. Stepping, Whisker, and Cylinder tests were carried out to determine the motor function, and the expression of tyrosine hydroxylase was detected by immunohistochemistry. The levels of multiple proinflammatory cytokines, oxidative stress related factors and proteins involved in Toll-like receptor (TLR)/nuclear factor kappa B (NF-κB) pathway were measured. The synergistic effect of environment enrichment on diosgenin was also investigated. Results: Intra-striatal injection of LPS caused motor deficits in rats, induced inflammatory response and oxidative stress response, and activated the TLR/NF-κB pathway both in vivo and in vitro. Diosgenin could attenuate the LPS-induced alterations. Enriched environment enhanced the effect of diosgenin to ameliorate the LPS-induced motor deficits in rats and decreased the protein levels of TLR2, TLR4, and nuclear NF-κB in diosgenin treated PD rats. Conclusion: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κB signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κB signaling pathway.
Pages 957-971
Lin Wang, Fang-Xiao Shi, Wei-Qi Xu, Yun Cao, Na Li, Man Li, Qun Wang, Jian-Zhi Wang, Qing Tian, Li-Kai Yu, Xin-Wen Zhou
The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R-/- Mice
Abstract: Alzheimer’s disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1-42 mice compared with that of WT-Aβ1-42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1-42 mice than that in WT-Aβ1-42 mice. CB2R activation could decrease Aβ1-40 and Aβ1-42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD.
Pages 973-980
Jagan A. Pillai, Brian S. Appleby, Jiri Safar, James B. Leverenz (Handling Associate Editor: Annachiara Cagnin)
Rapidly Progressive Alzheimer’s Disease in Two Distinct Autopsy Cohorts
Abstract: Background: A rapidly progressive phenotype of Alzheimer’s disease (AD) has been described in some prion disease cohorts. Limited information regarding rapidly progressive AD (rpAD) is available from longitudinal national cohorts. Objective: To compare the clinical characteristics of rpAD in two different national cohorts. Methods: A retrospective analysis was performed on AD subjects with available neuropathology in the National Alzheimer’s Coordinating Center (NACC) database and among neuropathologically characterized AD cases from the National Prion Disease Pathology Surveillance Center (NPDPSC) that were evaluated for suspected prion disease. In the NACC cohort, rpAD was delineated by the lower 10th percentile of follow up duration from pre-dementia to death duration among subjects meeting pathological diagnosis of AD. Results: rpAD from the NPDPSC had a shorter mean symptom duration than the NACC identified rpAD cases (11.6 months versus 62.4 months) and were also younger at the time of their death (60.0 versus 81.8 years). NACC identified rpAD subjects, beginning from a predementia stage, had slower rate of MMSE change per year than NPDPSC cases (2.5 versus 6.0 points). Conclusions: rpAD constitute an important subset of AD subjects in whom a rapid course of symptomatic clinical decline is noted, as confirmed in both national cohorts. rpAD was best characterized by survival time (≤ 3 years), as there were clear differences between the rpAD cohorts in terms of symptom duration, age at death, and MMSE change per year, likely due to the strong selection biases. rpAD could shed light on the biology of rate of progression in AD.
Pages 981-993
Grazia Daniela Femminella, Genevieve Taylor-Davies, James Scott, Paul Edison for the Alzheimer’s Disease Neuroimaging Initiative
Do Cardiometabolic Risk Factors Influence Amyloid, Tau, and Neuronal Function in APOE4 Carriers and Non-Carriers in Alzheimer’s Disease Trajectory?
Abstract: Cardiovascular risk could be calculated using Qrisk2. It is suggested that cardiovascular risk factors influence the progression of Alzheimer’s disease (AD). However, studies have not specifically evaluated the influence of cardiovascular risk using Qrisk2 on neuropathological progression and AD biomarkers. The aim of the study was to evaluate the influence of cardiovascular risk factors using Qrisk2 on CSF amyloid-β (Aβ) and tau, 18F-AV45-PET, 18F-FDG-PET, MRI, and cognitive measures in APOE4 negative cognitively normal and mild cognitive impairment (MCI) subjects. 614 cognitively normal, early, and late MCI subjects were selected from the ADNI cohort with a 2-year follow-up. CSF Aβ and tau, 18F-AV45-PET, 18F-FDG-PET, MRI, and cognitive measures along with modified Qrisk2 were evaluated. APOE4 non-carrier, high cardiovascular risk sub-group of early and late MCI and cognitively normal subjects, demonstrated worse biomarker and cognitive profile at baseline and during follow up compared to low cardiovascular risk group. Additionally, similar pattern was also observed in APOE4 carriers. We demonstrated that Qrisk2 and APOE4 were independent predictors of biomarker and clinical progression in AD trajectory. High cardiovascular risk is associated with biomarker changes in APOE4 non-carriers in prodromal AD, which may suggest that treatment of cardiovascular risk is an effective prevention strategy even in APOE4 negative subjects and may influence disease progression independent of amyloid pathology. Demonstration of accelerated neuropathological changes in both APOE4 carriers and non-carriers suggest that focusing on modifiable cardiovascular risk factors is an effective preventative strategy while we are eagerly wait for new treatments.
Pages 995-1007
Julia Derk, Keria Bermudez Hernandez, Moises Rodriguez, Meilun He, Hyunwook Koh, Andisheh Abedini, Huilin Li, David Fenyö, Ann Marie Schmidt (Handling Associate Editor: Wei Li)
Diaphanous 1 (DIAPH1) Is Highly Expressed in the Aged Human Medial Temporal Cortex and Upregulated in Myeloid Cells During Alzheimer’s Disease
Abstract: Background: The receptor for advanced glycation end products (RAGE) is linked to cellular stress and inflammation during Alzheimer’s disease (AD). RAGE signals through Diaphanous-1 (DIAPH1); however, the expression of DIAPH1 in the healthy and AD human brain is yet to be methodically addressed. Objective: To delineate the cell- and disease-state specific expression of DIAPH1 in the human medial temporal cortex during healthy aging and AD. Methods: We used semi-quantitative immunohistochemistry in the human medial temporal cortex paired with widefield and confocal microscopy and automated analyses to determine colocalization and relative expression of DIAPH1 with key cell markers and molecules in the brains of subjects with AD versus age-matched controls. Results: We report robust colocalization of DIAPH1 with myeloid cells and increased expression during AD, which strongly correlated to increased neutral lipids and morphology of inflamed myeloid cells. DIAPH1 moderately colocalized with markers of endothelial cells, astrocytes, neurons, and oligodendrocytes. Discussion: Our findings localize DIAPH1 particularly to myeloid cells in the CNS, especially in AD in the locations of lipid droplet accumulation, thereby implicating RAGE-DIAPH1 signaling in dysregulated lipid metabolism and morphological changes of inflamed myeloid cells in this disorder.
Pages 1009-1017
Irundika H.K. Dias, Caroline L. Brown, Kiran Shabir, M. Cristina Polidori, Helen R. Griffiths (Handling Associate Editor: Patrizia Mecocci)
miRNA 933 Expression by Endothelial Cells Is Increased by 27-Hydroxycholesterol and Is More Prevalent in Plasma from Dementia Patients
Abstract: Alzheimer’s disease (AD) etiology is complex; gene and environmental risk factors may interact to predispose to disease. From single nucleotide polymorphism analyses and genome-wide association studies, a number of candidate risk genes for the onset of AD have been identified and cluster around lipid metabolism and inflammation. We hypothesized that endothelial cells which line the blood-brain barrier are likely to be critical mediators of systemic metabolism within the brain. Therefore, we have studied the effect of 27 hydroxycholesterol (27-OHC) on microvascular endothelial cell (HMVEC) redox state, inflammatory cytokine secretion, and microRNA (miR) expression. Using a transwell method, we have studied directional secretion profiles for the proinflammatory cytokines TNFα and IL-6 and confirmed that 27-OHC induces discrete and directional inflammatory molecular signatures from HMVEC. The lipids caused depletion of cellular glutathione and cytokine secretion is HMVEC-redox state-dependent. Discovery miR expression changes in HMVEC with and without 27-OHC treatment was undertaken. We selected three genes for further analysis by qPCR; miR-144 and 146 expression, which are anti-inflammatory and redox regulating modulators, were not affected significantly by 27-OHC. However, increased expression of a putative neurotrophic regulatory factor miR933 in HMVEC with 27-OHC was confirmed by qPCR. In plasma from patients with dementia, all three miR were found at significantly elevated levels compared to healthy older adults. These data highlight that 27-OHC has an important regulatory effect on endothelial microvascular cells to increase expression of a miR (-933) and secretion of inflammatory cytokines that are elevated in plasma from dementia patients.
Pages 1019-1048
BON Conference Abstracts, 11-13 July 2018, Downing College, Cambridge University, UK
