Journal of Alzheimer's Disease - Volume 64, issue 3

Authors: Lu, Hanna | Ni, Xi | Fung, Ada W.T. | Lam, Linda C.W.

Article Type: Research Article

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). Methods: 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. Show more

Keywords: Capacity, cortical thickness, learning, retention, working memory

DOI: 10.3233/JAD-180225

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 815-826, 2018

Authors: Bohlken, Jens | Jacob, Louis | van den Bussche, Hendrik | Kostev, Karel

Article Type: Research Article

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. Show more

Keywords: Anti-dementia therapy initiation, dementia, Germany, polypharmacy, retrospective study

DOI: 10.3233/JAD-180382

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 827-833, 2018

Authors: Hutton, Craig P. | Lemon, Jennifer A. | Sakic, Boris | Rollo, C. David | Boreham, Douglas R. | Fahnestock, Margaret | Wojtowicz, J. Martin | Becker, Suzanna

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, anhedonia, anxiety, dietary supplements, learning, memory, mice, mild cognitive impairment, reversal learning, transgenic, working memory

DOI: 10.3233/JAD-170921

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 835-857, 2018

Authors: Schartmann, Elena | Schemmert, Sarah | Niemietz, Nicole | Honold, Dominik | Ziehm, Tamar | Tusche, Markus | Elfgen, Anne | Gering, Ian | Brener, Oleksandr | Shah, Nadim Joni | Langen, Karl-Josef | Kutzsche, Janine | Willbold, Dieter | Willuweit, Antje

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, amyloid-β , D-enantiomeric peptides, pharmacokinetic profile

DOI: 10.3233/JAD-180165

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 859-873, 2018

Authors: Beauchet, Olivier | Sekhon, Harmehr | Barden, John | Liu-Ambrose, Teresa | Chester, Victoria L. | Szturm, Tony | Grenier, Sébastien | Léonard, Guillaume | Bherer, Louis | Allali, Gilles | Canadian Gait Consortium

Article Type: Research Article

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 abnormalWHR(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. Show more

Keywords: Cognitive disorders, gait disorders, meta-analysis, prediction

DOI: 10.3233/JAD-180203

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 875-887, 2018

Authors: Paquet, Claire | Bouaziz-Amar, Elodie | Cognat, Emmanuel | Volpe-Gillot, Lisette | Haddad, Victor | Mahieux, Florence | Dekimeche, Siham | Defontaines, Benedicte | Chabriat, Hugues | Belin, Catherine | Texeira, Antonio | Goutagny, Stephane | Questel, Frank | Azuar, Julien | Sellier, Pierre-Olivier | Laplanche, Jean-Louis | Hugon, Jacques | Dumurgier, Julien

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, cohort, epidemiology, SNAP

DOI: 10.3233/JAD-180240

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 889-897, 2018

Authors: Ritchie, Craig W. | Khandker, Rezaul K. | Pike, James | Black, Christopher M. | Jones, Eddie | Ambegaonkar, Baishali M.

Article Type: Research Article

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. Show more

Keywords: ADAS-Cog, Alzheimer’s disease, dementia, healthcare resource utilization, patient chart review, real-world practice patterns

DOI: 10.3233/JAD-180306

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 899-910, 2018

Authors: Chen, Yuanxin | Lim, Patrick | Rogers, Kem A. | Rutt, Brian K. | Ronald, John A.

Article Type: Research Article

Abstract: Hypercholesterolemia has been identified as a risk factor 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. Show more

Keywords: Alzheimer’s disease, MRI, cholesterol, rabbit model, amyloid-β plaques

DOI: 10.3233/JAD-180207

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 911-923, 2018

Authors: Strohmaier, Urs | Keller, Felix | Kilimann, Ingo | Michalowsky, Bernhard | Wucherer, Diana | Zwingmann, Ina | Teipel, Stefan | Hoffmann, Wolfgang | Thyrian, Jochen René

Article Type: Research Article

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 used 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. Show more

Keywords: Dementia, neuroimaging, primary care, specialized care, utilisation

DOI: 10.3233/JAD-180196

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 925-932, 2018

Authors: Garrido, Sandra | Stevens, Catherine J. | Chang, Esther | Dunne, Laura | Perz, Janette

Article Type: Research Article

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 was measured, and behavioural responses continuously observed. 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 impairment. 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. Show more

Keywords: Dementia, depression, individual differences, music, playlists

DOI: 10.3233/JAD-180084

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 933-941, 2018

Authors: Li, Bingyu | Xu, Pengli | Wu, Shuyan | Jiang, Zhixian | Huang, Zhijian | Li, Qian | Chen, Danhong

Article Type: Research Article

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-κ B) 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-κ B 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-κ B in diosgenin treated PD rats. Conclusion: Diosgenin had a beneficial effect in LPS-induced rat PD models, by suppressing the TLR/NF-κ B signaling pathway. Environmental enrichment could play a synergistic effect with diosgenin, by enhancing the inhibitory effect of diosgenin on the TLR/ NF-κ B signaling pathway. Show more

Keywords: Diosgenin, environment enrichment, lipopolysaccharide, Parkinson’s disease, Toll-like receptor/nuclear factor kappa B pathway

DOI: 10.3233/JAD-180330

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 943-955, 2018

Authors: Wang, Lin | Shi, Fang-Xiao | Xu, Wei-Qi | Cao, Yun | Li, Na | Li, Man | Wang, Qun | Wang, Jian-Zhi | Tian, Qing | Yu, Li-Kai | Zhou, Xin-Wen

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, amyloid-β degradation, angiotensin converting enzyme, type 2-cannabinoid receptors, insulin-degrading enzyme

DOI: 10.3233/JAD-180142

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 957-971, 2018

Authors: Pillai, Jagan A. | Appleby, Brian S. | Safar, Jiri | Leverenz, James B.

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, dementia, rapidly progressive dementia, rate of decline

DOI: 10.3233/JAD-180155

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 973-980, 2018

Authors: Femminella, Grazia Daniela | Taylor-Davies, Genevieve | Scott, James | Edison, Paul | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

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, 18 F-AV45-PET, 18 F-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, 18 F-AV45-PET, 18 F-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 eagerly waiting for new treatments. Show more

Keywords: Alzheimer’s disease, APOE4, biomarkers, cardiovascular disease, risk factors

DOI: 10.3233/JAD-180365

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 981-993, 2018

Authors: Derk, Julia | Bermudez Hernandez, Keria | Rodriguez, Moises | He, Meilun | Koh, Hyunwook | Abedini, Andisheh | Li, Huilin | Fenyö, David | Schmidt, Ann Marie

Article Type: Research Article

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 has 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. Show more

Keywords: Alzheimer’s disease, DIAPH1, myeloid cells, microglia, lipids, inflammation, RAGE

DOI: 10.3233/JAD-180088

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 995-1007, 2018

Authors: Dias, Irundika H.K. | Brown, Caroline L. | Shabir, Kiran | Polidori, M. Cristina | Griffiths, Helen R.

Article Type: Research Article

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 change 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. Show more

Keywords: Alzheimer’s disease, dementia, glutathione, inflammation, miRNA, neurotrophic factor, oxysterol, redox, vascular

DOI: 10.3233/JAD-180201

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 1009-1017, 2018

Article Type: Abstract

DOI: 10.3233/JAD-189006

Citation: Journal of Alzheimer's Disease, vol. 64, no. 3, pp. 1019-1048, 2018