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

Authors: Pepperberg, David R.

Article Type: Research Article

Abstract: Cerebral hypoperfusion-induced hypoxia, a condition that impairs oxygen utilization and thus ATP production by mitochondrial oxidative phosphorylation (oxphos), is thought to contribute to neural degeneration in Alzheimer’s disease. However, hypoxia upregulates the generation of amyloid-β (Aβ), a group of peptides known to impair/inhibit the electron transport chain (ETC) of reactions that support oxphos in the inner mitochondrial membrane (IMM). This is a hypothesis paper that reconciles the hypoxia-induced upregulation of Aβ with Aβ’s ETC-inhibiting action and, specifically, posits an oxphos-enhancing effect of this inhibition under conditions of newly developing or otherwise mild hypoxia. This effect is typically transient; that is, …under conditions of prolonged or severe hypoxia, the oxphos-enhancing activity is overwhelmed by Aβ’s well-known toxic actions on mitochondria and other cellular components. The hypothesis is motivated by evidence that the IMM transmembrane potential Ψ m , an important determinant of ETC activity, exhibits heterogeneity, i.e., a range of values, among a given local population of mitochondria. It specifically proposes that during oxygen limitation, Aβ selectively inactivates ETC complexes in mitochondria that exhibit relatively low absolute values of Ψ m , thereby suppressing oxygen binding and consumption by complex IV of the ETC in these mitochondria. This effect of Aβ on low-Ψ m mitochondria is hypothesized to spare hypoxia-limited oxygen for oxphos-enabling utilization by the ETC of the remaining active, higher-Ψ m local mitochondria, and thereby to increase overall ATP generated collectively by the local mitochondrial population, i.e., to ameliorate hypoxia-induced oxphos reduction. The protective action of Aβ hypothesized here may slow the early development of hypoxia-associated cellular deterioration/loss in Alzheimer’s disease and perhaps other neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, amyloid-β, hypoxia, mitochondrial transmembrane potential, neurodegeneration, oxidative phosphorylation

DOI: 10.3233/JAD-190476

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

Authors: Nitzan, Keren | Benhamron, Sandrine | Valitsky, Michael | Kesner, Eyal | Lichtenstein, Michal | Ben-Zvi, Ayal | Ella, Ezra | Segalstein, Yehudit | Saada, Ann | Lorberboum-Galski, Haya | Rosenmann, Hanna

Article Type: Research Article

Abstract: Pathogenesis of neurodegenerative diseases involves dysfunction of mitochondria, one of the most important cell organelles in the brain, with its most prominent roles in producing energy and regulating cellular metabolism. Here we investigated the effect of transferring active intact mitochondria as a potential therapy for Alzheimer’s disease (AD), in order to correct as many mitochondrial functions as possible, rather than a mono-drug related therapy. For this purpose, AD-mice (amyloid-β intracerebroventricularly injected) were treated intravenously (IV) with fresh human isolated mitochondria. One to two weeks later, a significantly better cognitive performance was noticed in the mitochondria treated AD-mice relative to vehicle …treated AD-mice, approaching the performance of non-AD mice. We also detected a significant decrease in neuronal loss and reduced gliosis in the hippocampus of treated mice relative to untreated AD-mice. An amelioration of the mitochondrial dysfunction in brain was noticed by the increase of citrate-synthase and cytochrome c oxidase activities relative to untreated AD-mice, reaching activity levels of non-AD-mice. Increased mitochondrial activity was also detected in the liver of mitochondria treated mice. No treatment-related toxicity was noted. Thus, IV mitochondrial transfer may possibly offer a novel therapeutic approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-ICV model, cognition, mitochondria, mitochondrial-transfer

DOI: 10.3233/JAD-190853

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Castellani, Rudy J. | Smith, Margaret | Bailey, Kristi | Perry, George | deJong, Joyce L.

Article Type: Research Article

Abstract: Traumatic brain injury (TBI) is widely assumed to be causal in neurodegenerative disease, based on epidemiological surveys demonstrating an increased risk of Alzheimer disease (AD) following TBI, and on recent theories surrounding repetitive head movement. We tested this assumption by evaluating 30 consecutive forensic examinations in which neuropathology consultation was sought, and in which a history of remote TBI was uncovered during the course of the investigation. In this series, there was a high frequency of psychiatric co-morbidities (100%), remote contusion (90%), and seizures (63%). Extent of proteinopathy showed no differences with age-matched controls. A subset of the cases showed …focal geographic tauopathy that correlated with older age at autopsy, but had no correlation with clinical signs, and was minimal in comparison with the encephalomalacia secondary to trauma. The results suggest that cerebral contusion and post-traumatic epilepsy may be over-represented in civilian TBI, while structural brain damage from trauma is the predominant cause of morbidity following TBI. We found no evidence that TBI initiates a progressive proteinopathy. Show more

Keywords: Amyloid-β, contusion, epilepsy, neurodegenerative disease, phosphorylated tau, traumatic brain injury

DOI: 10.3233/JAD-190782

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Elshatoury, Heba | Avots, Egils | Anbarjafari, Gholamreza | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: In this research work, machine learning techniques are used to classify magnetic resonance imaging brain scans of people with Alzheimer’s disease. This work deals with binary classification between Alzheimer’s disease and cognitively normal. Supervised learning algorithms were used to train classifiers in which the accuracies are being compared. The database used is from The Alzheimer’s Disease Neuroimaging Initiative (ADNI). Histogram is used for all slices of all images. Based on the highest performance, specific slices were selected for further examination. Majority voting and weighted voting is applied in which the accuracy is calculated and the best result is 69.5% for …majority voting. Show more

Keywords: Alzheimer’s disease, computer vision, feature extraction, individual grey matter, machine learning, magnetic resonance imaging

DOI: 10.3233/JAD-190704

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

Authors: Seblova, Dominika | Brayne, Carol | Machů, Vendula | Kuklová, Marie | Kopecek, Miloslav | Cermakova, Pavla

Article Type: Research Article

Abstract: Background: Studies from North America and Western Europe suggest stable or declining trends in impaired cognition across birth cohorts. Objective: We aimed to examine changes in the age-specific prevalence of cognitive impairment in the Czech Republic. Methods: The study used two samples from the population-based Czech Survey on Health, Ageing and Retirement in Europe. Age-specific prevalence of cognitive impairment (defined based on scores in verbal fluency, immediate recall, delayed recall, and temporal orientation) was compared between participants in wave 2 (2006/2007; n  = 1,107) and wave 6 (2015; n  = 3,104). Logistic regression was used to estimate the …association between the wave and cognitive impairment, step-wise adjusting for sociodemographic and clinical characteristics. Multiple sensitivity analyses, focusing on alternative operationalizations of relative cognitive impairment, impact of missing cognitive data, and survival bias, were carried out. Results: The most conservative estimate suggested that the age-specific prevalence of cognitive impairment declined by one fifth, from 11% in 2006/2007 to 9% in 2015. Decline was observed in all sensitivity analyses. The change was associated with differences in physical inactivity, management of high blood cholesterol, and increases in length education. Conclusion: Older adults in the Czech Republic, a country situated in the Central and Eastern European region, have achieved positive developments in cognitive aging. Longer education, better management of cardiovascular factors, and reduced physical inactivity seem to be of key importance. Show more

Keywords: Cognitive impairment, Czech Republic, epidemiology, prevalence, trends

DOI: 10.3233/JAD-190688

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Turriziani, Patrizia | Smirni, Daniela | Mangano, Giuseppa Renata | Zappalà, Giuseppe | Giustiniani, Andreina | Cipolotti, Lisa | Oliveri, Massimiliano

Article Type: Research Article

Abstract: Background: The lack of effective pharmacological or behavioral interventions for memory impairments associated with Alzheimer’s disease (AD) emphasizes the need for the investigation of approaches based on neuromodulation. Objective: This study examined the effects of inhibitory repetitive transcranial magnetic stimulation (rTMS) of prefrontal cortex on recognition memory in AD patients. Methods: In a first experiment, 24 mild AD patients received sham and real 1Hz rTMS over the left and right dorsolateral prefrontal cortex (DLPFC), in different sessions, between encoding and retrieval phases of a non-verbal recognition memory task. In a second experiment, another group of 14 …AD patients underwent sham controlled repeated sessions of 1Hz rTMS of the right DLPFC across a two week treatment. Non-verbal recognition memory task was performed at baseline, at the end of the two weeks period and at a follow up of 1 month. Results: Right real rTMS significantly improved memory performance compared to right sham rTMS (p  = 0.001). Left real rTMS left the memory performance unchanged as compared with left sham rTMS (p  = 0.46). The two sham conditions did not differ between each other (p  = 0.24). In the second experiment, AD patients treated with real rTMS showed an improvement of memory performance at the end of the two weeks treatment (p  = 0.0009), that persisted at 1-month follow-up (p  = 0.002). Conclusion: These findings provide evidence that inhibitory rTMS over the right DLPFC can improve recognition memory function in AD patients. They also suggest the importance of a new approach of non-invasive brain stimulation as a promising treatment in AD. Show more

Keywords: Alzheimer’s disease, prefrontal cortex, recognition memory, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-190888

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

Authors: D’Cunha, Nathan M. | McKune, Andrew J. | Isbel, Stephen | Kellett, Jane | Georgousopoulou, Ekavi N. | Naumovski, Nenad

Article Type: Research Article

Abstract: The use of existing public spaces by people living with dementia, such as museums and art galleries, are becoming popular due to their ability to facilitate programs which promote social engagement and inclusion. However, few studies have investigated physiological outcomes of art gallery-based programs. Using a quasi-experimental design, the present study aimed to investigate the levels of salivary biomarkers of cortisol and interleukin-6, quality of life (QoL), depressive symptoms, cognition, and wellbeing, after attending the National Gallery of Australia (NGA) Art and Dementia program. Twenty-eight people living with dementia, each supported by a carer or family member, were recruited for …a six-week program and were followed up at twelve weeks. In total, 25 participants (17 female; mean age 84.6±7.27 years) completed the study, and 22 provided viable saliva samples. The waking to evening salivary cortisol ratio was higher post-intervention (p  = 0.033), and returned to baseline levels at follow-up (p  = 1.00), indicating a more dynamic salivary cortisol rhythm in response to the six-week program. Interleukin-6 levels remained unchanged (p  = 0.664). No improvements in QoL (DEMQOL-Carer) were observed between baseline and post-intervention (p  = 0.076). However, self-reported depressive symptoms decreased post-intervention compared with baseline (p  = 0.015), and memory (immediate recall) (p  = 0.009) and verbal fluency (p  = 0.027) improved between the same timepoints. The NGA Art and Dementia program appears to have quantifiable benefits, including improved hypothalamic-pituitary-adrenal axis function, justifying a need for longer controlled trial inclusive of physiological outcomes. Show more

Keywords: Alzheimer’s disease, art, cognitive function, cortisol, dementia, psychophysiology, quality of life

DOI: 10.3233/JAD-190784

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

Authors: Orgeta, Vasiliki | Tuijt, Remco | Leung, Phuong | Verdaguer, Elisabet Sole | Gould, Rebecca L. | Jones, Rebecca | Livingston, Gill

Article Type: Research Article

Abstract: Engaging in meaningful and enjoyable activities is an important contributor to well-being and maintaining good quality of life. There is a paucity of randomized controlled trials of interventions supporting people with mild dementia to engage in meaningful and purposeful activity. The aim of this study was to assess whether Behavioral Activation (BA) is an acceptable psychological intervention for people with mild dementia and whether a large-scale trial is feasible. Participants were randomly assigned to BA (n  = 42) or treatment as usual (TAU) (n  = 21). BA aimed at increasing engagement in enjoyable and meaningful activity, and preventing low mood. Follow-up was …at 3 and 6 months. Assessors were blind to treatment allocation (trial registration number: ISRCTN75503960). Retention rate was above 80% at both assessment time points. Treatment acceptability and credibility were high. Depressive symptoms remained unchanged in both groups. There was evidence of improvement associated with BA for every day function (–3.92, 95% Confidence Interval (CI) –6.87 to –0.97), and engagement in meaningful and enjoyable activity (5.08, 95% CI 0.99 to 9.16) post-treatment (3 months) in comparison to TAU. Both carer-rated patient health-related quality of life (0.16, 95% CI 0.04 to 0.28) and physical health (11.31, 95% CI 2.03 to 20.59) showed evidence of improvement at 3 months. Improvements in meaningful and enjoyable activity were maintained at 6 months. BA for people with mild dementia is feasible and acceptable and may be associated with clinically significant changes in function and quality of life. A full scale randomized controlled trial of clinical effectiveness is now needed. Show more

Keywords: Acceptability, activity scheduling, behavioral activation, behavioral therapy, dementia, feasibility, low mood, pleasant events, randomized controlled trial

DOI: 10.3233/JAD-190696

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

Authors: van Husen, Lea S. | Schedin-Weiss, Sophia | Trung, Minh Nguyen | Kazmi, Manija | Winblad, Bengt | Sakmar, Thomas P. | Elsässer, Simon J. | Tjernberg, Lars O.

Article Type: Research Article

Abstract: The amyloid-β protein precursor (AβPP) is critical in the pathophysiology of Alzheimer’s disease (AD), since two-step proteolytic processing of AβPP generates the neurotoxic amyloid-β peptide (Aβ). We developed a dual fluorescence labeling system to study the exact subcellular location of γ -secretase cleavage of AβPP. The C-terminal tail of AβPP was fluorescently labeled using a SNAP-tag, while the Aβ region of AβPP was fluorescently tagged with a dye at a genetically-encoded noncanonical amino acid (ncAA). The ncAA was introduced at specific positions in AβPP using a genetic code expansion strategy and afterwards, the reactive side-chain of the ncAA was coupled …to the dye using a bioorthogonal labeling chemistry. In proof-of-concept experiments, HEK293T cells were transfected with plasmids containing engineered AβPP harboring an amber mutation and an amber codon suppression system with an evolved tRNA synthetase/tRNA pair and grown in the presence of a lysine-derived ncAA. Processing of the AβPP variants was validated with ELISA and immunoblotting, and seven AβPP mutants that showed similar cleavage pattern as wild-type AβPP were identified. The AβPP mutant was fluorescently labeled with 6-methyl-tetrazine-BDP-FL and TMR-Star at the ncAA and SNAP-tag, respectively. Using this approach, AβPP was fluorescently labeled at two sites in living cells with minimal background to allow monitoring of Aβ and C-terminal cleavage products simultaneously. The method described provides a powerful tool to label Aβ with minimal perturbations of its processing, thus enabling studies of the trafficking of the cleavage products of AβPP. Show more

Keywords: Alzheimer’s disease, amber codon, amyloid-β precursor protein, cell biology, click chemistry, confocal microscopy, γ-secretase

DOI: 10.3233/JAD-190898

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

Authors: Aulston, Brent | Liu, Qing | Mante, Michael | Florio, Jazmin | Rissman, Robert A. | Yuan, Shauna H.

Article Type: Research Article

Abstract: Extracellular vesicles (EVs) are a heterogeneous group of secreted particles consisting of microvesicles, which are released by budding of the cellular membrane, and exosomes, which are secreted through exocytosis from multivesicular bodies. EV cargo consists of a wide range of proteins and nucleic acids that can be transferred between cells. Importantly, EVs may be pathogenically involved in neurodegenerative diseases such as Alzheimer’s disease (AD). While EVs derived from AD neurons have been found to be neurotoxic in vitro , little is known about the pathological consequences of AD EVs in vivo . Furthermore, although all known familial AD (fAD) mutations …involve either amyloid-β protein precursor (AβPP) or the machinery that processes AβPP, hyperphosphorylation of the microtubule associated protein tau appears to play a critical role in fAD-associated neurodegeneration, and previous reports suggest EVs may propagate tau pathology in the AD brain. Therefore, we hypothesized that fAD EVs may have a mechanistic involvement in the development of fAD-associated tau pathology. To test this, we isolated EVs from iPSC-derived neuronal cultures generated from an fAD patient harboring a A246E mutation to presenilin-1 and stereotactically injected these EVs into the hippocampi of wild-type C57BL/6 mice. Five weeks after injection, mice were euthanized and pathology evaluated. Mice injected with fAD EVs displayed increased tau phosphorylation at multiple sites relative to PBS and non-disease control EV injected groups. Moreover, fAD EV injected hippocampi contained significantly more tau inclusions in the CA1 hippocampal neuronal field than controls. In total, these findings identify EVs as a potential mediator of fAD-associated tau dysregulation and warrant future studies to investigate the therapeutic potential of EV-targeted treatments for fAD. Show more

Keywords: Alzheimer’s disease, C57BL/6, extracellular vesicles induced pluripotent stem cells, tau, tauopathy

DOI: 10.3233/JAD-190656

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

Authors: Vonk, Jet M.J. | Rentería, Miguel Arce | Medina, Valerie M. | Pericak-Vance, Margaret A. | Byrd, Goldie S. | Haines, Jonathan | Brickman, Adam M. | Manly, Jennifer J.

Article Type: Research Article

Abstract: Background: The APOE ɛ 4 allele is a well-known risk factor for Alzheimer’s disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. Objective: To test if higher educational level buffers the effect of APOE ɛ 4 on cognition among older non-Hispanic Blacks. Methods: Participants were 849 non-demented older non-Hispanic Blacks (38.3% APOE ɛ 4 +), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between APOE ɛ …4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. Results: Education buffered the effects of the APOE ɛ 4 allele, such that there was no impact of APOE ɛ 4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed—although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. Conclusion: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment. Show more

Keywords: African American, Alzheimer’s disease, APOE, cognitive reserve, educational attainment, episodic memory, genetic risk, neuropsychological evaluation

DOI: 10.3233/JAD-190415

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

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Cognitive frailty (CF) is defined as simultaneous presence of physical frailty (PF) and cognitive impairment among older adults without dementia. Although white matter hyperintensities (WMH) as expressions of cerebral small vessel disease are associated with physical and cognitive decline and could manifest as CF, this association remains yet to be clarified. Objects: To clarify the association between CF and WMH among memory clinic patients. Methods: The subjects of this cross-sectional study were 121 cognitively normal (CN) and 212 mildly cognitively impaired (MCI) patients who presented to the Memory Clinic at the National Center for Geriatrics …and Gerontology of Japan. PF status was defined based on the definition proposed by Fried and colleagues. CF was defined as simultaneous presence of pre-PF or PF and MCI. WMH volumes were measured using an automatic segmentation application. Multiple liner regression analyses with adjustment for cardiovascular risk factors were performed. Results: Of all subjects, 77 (63.6%) and 22 (18.2%) CN patients and 132 (62.3%) and 65 (30.7%) MCI patients were categorized into pre-PF and PF, respectively. Multiple liner regression analysis showed that those with CF had higher WMH volumes than those without (β= 0.23). When categorized into six groups according to PF and cognitive status, the PF/CN (β= 0.15), pre-PF/MCI (β= 0.41), and PF/MCI (β= 0.34) groups had higher WMH volumes than the non-PF/CN group. Conclusions: This study showed increased WMH volumes in CF and PF, indicating that WMH could be one of the key underlying brain pathologies of CF. Show more

Keywords: Cognitive frailty, frailty syndrome, mild cognitive impairment, physical frailty, white matter hyperintensity

DOI: 10.3233/JAD-190622

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kehoe, Patrick G. | Al Mulhim, Noura | Zetterberg, Henrik | Blennow, Kaj | Miners, James S.

Article Type: Research Article

Abstract: Observations in autopsied brain tissue indicate that overactivation of the classical renin-angiotensin system (cRAS) and underactivity within regulatory RAS pathways (rRAS) are associated with pathology in Alzheimer’s disease (AD). The primary aim of this study was to investigate whether cerebrospinal fluid (CSF) markers of RAS are altered in AD in relation to established CSF markers of disease pathology (lower Aβ42 and elevated tau) and CSF markers of capillary dysfunction. We studied 40 controls and 40 AD cases grouped according to a biomarker profile (i.e., AD cases t-tau>400 pg/mL, pTau >60 pg/mL, and Aβ42 <550 pg/mL). Angiotensin-II converting enyme-1 …(ACE1) and ACE2 enzyme activity was measured using fluorogenic peptide substrates; sPDGFRβ and albumin level by sandwich ELISA and angiotensin-I (Ang-I), Ang-II, and Ang-(1-7) by direct ELISA. CSF Aβ42 , total, and phosphorylated tau levels were previously measured by INNOTEST sandwich ELISA. CSF ACE1 activity was significantly elevated in AD (p  = 0.008) and positively correlated with ACE2 in AD (r  = 0.420, p  = 0.007). CSF ACE1 weakly correlated with t-tau (r  = 0.294, p  = 0.066) and p-tau (r  = 0.329, p  = 0.038) but not with Aβ42 in the controls but not in AD. ACE1 correlated positively with sPDGFRβ (r  = 0.426, p  = 0.007), a marker of pericyte injury, and ACE2 correlated positively with albumin (r  = 0.422, p  = 0.008), a marker of blood-brain barrier integrity. CSF Ang-I, Ang-II, and Ang-(1-7) levels were unchanged in AD. This cross-sectional CSF study indicates RAS dysfunction in relation to capillary damage in AD. Show more

Keywords: Alzheimer’s disease, angiotensin-II, angiotensin-(1-7), angiotensin-II converting enyme-1 (ACE1), angiotensin-II converting enyme-2 (ACE2), cerebrospinal fluid, renin-angiotensin system

DOI: 10.3233/JAD-190721

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

Authors: Tian, Jing | Wang, Tienju | Wang, Qi | Guo, Lan | Du, Heng

Article Type: Research Article

Abstract: Hippocampal lesions including synaptic injury, neuroinflammation, and impaired neurogenesis are featured pathology closely associated with neuronal stress and cognitive impairment in Alzheimer’s disease (AD). Previous studies suggest that ghrelin and its receptor, growth hormone secretagogue receptor 1α (GHSR1α ), promote hippocampal synaptic function and neurogenesis. GHSR1α activation thus holds the potential to be a therapeutic avenue for the treatment of hippocampal pathology in AD; however, a comprehensive study on the preventive effect of MK0677 on hippocampal lesions in AD-related conditions is still lacking. In this study, we treated a transgenic mouse model of AD-like amyloidosis (5xFAD mice) at …the asymptomatic stage with MK0677, a potent ghrelin mimetic. We found that MK0677 fostered hippocampal neurogenesis in 5xFAD mice but observed little preventive function with regards to the development of hippocampal amyloid-β (Aβ) deposition, synaptic loss, microglial activation, or cognitive impairment. Furthermore, MK0677 at a dose of 3 mg/kg significantly increased 5xFAD mouse mortality. Despite enhanced hippocampal neurogenesis, MK0677 treatment has little beneficial effect to prevent hippocampal lesions or cognitive deficits against Aβ toxicity. This study, together with a failed large-scale clinical trial, suggests the ineffectiveness of MK0677 alone for AD prevention and treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, growth hormone secretagogue receptor 1α, hippocampus, MK0677

DOI: 10.3233/JAD-190779

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

Authors: Forbes, Harriet J. | Wong, Angel Y.S. | Morton, Caroline | Bhaskaran, Krishnan | Smeeth, Liam | Richards, Marcus | Schmidt, Sigrun A.J. | Langan, Sinéad M. | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: In the UK, an estimated one third of people with dementia have not received a diagnosis. Good evidence suggests that dementia risk is increased among widowed individuals; however, it is not clear if they are being diagnosed in routine primary care. Objective: This study aimed to investigate if bereavement influenced the probability of having received a dementia diagnosis. Methods: A population-based cohort study using UK electronic health records, between 1997 and 2017, among 247,586 opposite-sex partners. Those experiencing partner bereavement were matched (age, sex, and date of bereavement) to a non-bereaved person living in a …partnership. Multivariate cox regression was performed. Results: Partner bereavement was associated with an increased risk of receiving a diagnosis of dementia in the first three months (hazard ratio (HR) 1.43, 95% CI 1.20–1.71) and first six months (HR 1.24, 95% CI 1.09–1.41), while there was a small reduced risk of getting a dementia diagnosis over all follow-up (HR 0.94, 95% CI 0.89–0.98). Conclusions: Partner bereavement appears to lead to a short-term increased risk of the surviving partner receiving a diagnosis of dementia, suggesting that bereavement unmasks existing undiagnosed dementia. Over the longer term, however, bereaved individuals are less likely to have a diagnosis of dementia in their health records than non-bereaved individuals. Show more

Keywords: Bereavement, Clinical Practice Research Datalink, dementia, diagnosis, epidemiology

DOI: 10.3233/JAD-190571

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

Authors: Zhou, Guoyu | Zhao, Xinjing | Lou, Zhiyin | Zhou, Shengnian | Shan, Peiyan | Zheng, Ning | Yu, Xiaolin | Ma, Lin

Article Type: Research Article

Abstract: Background: Vasculature changes have been observed in Alzheimer’s disease (AD). AD-related vascular pathology might impair cerebral autoregulation (CA). Objective: This study was designed to evaluate CA of AD patients by using transcranial doppler (TCD). Methods: A total of 61 participants were included in the study, including 31 AD patients and 30 controls. The trend curves of cerebral blood flow velocities (CBFV), pulsatility index, and resistance index were obtained using TCD during supine-to-standing posture changes. CA was measured by the changes of CBFV curves during supine-to-standing test. Results: There were two spikes named X spike …and W spike that appeared in the CBFV curve when the subjects stood abruptly. The slope of the X spike descending branch, the slope of the W spike ascending branch, and the angle between X and W spikes (α angle), showed significant differences between the experimental and control groups (2.34±0.99 versus 3.15±1.61 cm/s2 , p  = 0.021; 2.31±0.81 versus 3.38±1.18 cm/s2 , p  < 0.001; and 52.71±20.26 versus 41.4±12.87 degrees, p  = 0.012, respectively). ROC analysis showed that AUCα angle is 0.664 (p  = 0.028) and that AUCSAB and AUCadjustedSAB are 0.775 and 0.738, respectively (both p  < 0.001). Conclusions: Our study demonstrated that supine-to-standing TCD test is a valuable tool for the evaluation of CA in AD patients. Impaired CA in AD patients manifested as decreased efficiency of changes in the CBFV curve. Neurovascular units were involved in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, cerebral autoregulation, supine-to-standing test, transcranial Doppler

DOI: 10.3233/JAD-190296

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Yoshida, Koji | Hata, Yukiko | Ichimata, Shojiro | Nishida, Naoki

Article Type: Research Article

Abstract: Background: Aggregation of abnormal phosphorylated tau in brain stem areas may be a possible early pathological manifestation of Alzheimer’s disease (AD). Objective: This study aimed to explore the prevalence of cases with AD-related pathology in subjects <40 years of age and to explore the association of such pathology, neuropsychiatric symptoms, and APOE genotype. Method: We conducted brain immunohistochemistry for 189 cases <40 years of age (mean±standard deviation age 25.3±13.1 years). Tau positive cases were then assessed for the distribution of tau pathology in the locus ceruleus (LC), raphe nucleus (RN), and entorhinal cortex (ErC), and …the distinction between neuronal threads and cellular inclusions. Apolipoprotein E (APOE ) genotype was also examined. Results: Tau pathology was detected in 135 cases (71.4%; 13–39 years; only LC, 23 cases; only RN, 4 cases; only ErC, 35 cases; LC+RN, 3 cases; LC+ErC, 57 cases; all three regions, 10 cases). The prevalence of thread pathology was higher than that of cellular inclusions. Significantly higher prevalence of the APOE ɛ 2 allele were found in 10–39 years of age natural death cases (p  < 0.05). Amyloid-β deposition was found in only 7 cases, along with a significantly high frequency of the ɛ 4 allele (p  < 0.05). While a past history of psychiatric disease was a significant risk factor for suicide, AD-related pathology was not associated with suicide. Conclusions: Both the brain stem and entorhinal cortex was the initial site of tau pathology in many younger subjects. AD-related pathology may not be a significant accelerating factor for suicide in younger subjects. Show more

Keywords: Alzheimer’s disease, amyloid-β, ApoE, neuropathology, suicide, tau

DOI: 10.3233/JAD-190196

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

Authors: Liu, Xi-Xi | Jiao, Bin | Liao, Xin-Xin | Guo, Li-Na | Yuan, Zhen-Hua | Wang, Xin | Xiao, Xue-Wen | Zhang, Xin-Yue | Tang, Bei-Sha | Shen, Lu

Article Type: Research Article

Abstract: Recent studies found that poor oral hygiene was associated with increased risk of dementia, and the number of oral bacteria significantly increased in the brain tissues of patients with Alzheimer’s disease (AD), suggesting that the oral microbiota may play an important role in the pathogenesis of AD. However, the actual composition of oral bacteria communities in patients with AD and whether these oral bacteria are associated with disease severity remain largely unknown. Also, the APOE ɛ 4 polymorphism is a strong risk factor for sporadic AD, and it would be pertinent to see if the bacterial flora was different …in those patients who were APOE ɛ 4 positive. A total of 78 subjects were recruited in this study, including 39 patients with AD and 39 healthy controls. Saliva was collected from each subject. 16S ribosomal RNA (16S rRNA) sequencing was conducted to analyze the salivary microbiota, and Sanger sequencing was performed to analyze the APOE genotype. There was a significantly lower richness and diversity of saliva microbiota detected in AD patients than healthy controls. The relative abundance of Moraxella , Leptotrichia , and Sphaerochaeta in the saliva of AD patients greatly increased, whereas that of Rothia was significantly reduced. Compared with APOE ɛ 4 (–) patients, the level of Abiotrophia and Desulfomicrobium was comparatively abundant, while Actinobacillus and Actinomyces decreased significantly in patients carrying the APOE ɛ 4. No bacteria were found to be associated with the severity of AD. This is the first study to analyze the salivary microorganisms in patients with AD, and we discovered that the composition of salivary microbiome was altered in AD, providing further support for the role of the oral microbiome in AD development. Show more

Keywords: Alzheimer’s disease, APOE , oral microbiome, 16S rRNA

DOI: 10.3233/JAD-190587

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Rossini, Paolo Maria | Cappa, Stefano F. | Lattanzio, Fabrizia | Perani, Daniela | Spadin, Patrizia | Tagliavini, Fabrizio | Vanacore, Nicola

Article Type: Research Article

Abstract: Alzheimer’s disease is the most common age-related neurodegenerative disorder and its burden on patients, families, and society grows significantly with lifespan. Early modifications of risk-enhancing lifestyles and treatment initiation expand personal autonomy and reduce management costs. Many clinical trials with potentially disease-modifying drugs are devoted to mild cognitive impairment (MCI) prodromal-to-Alzheimer’s disease. The identification of biomarkers for early diagnosis may thus be crucial for early intervention and identification of high-risk subjects, the most appropriate target of new drugs as soon as they will be discovered. INTERCEPTOR is a strategic project by the Italian Ministry of Health and the Italian Medicines …Agency (AIFA), aiming to validate the best combination (highly accurate, non-invasive, available on the whole national territory and financially sustainable) of biomarkers and organizational model for early diagnosis. 500 MCI subjects will be enrolled at baseline and followed-up for 3 years for at least 400 of them in order to define a “hub & spoke” nationwide model with recruiting (spokes) centers for MCI identification and expert (hubs) centers for risk diagnosis. Show more

Keywords: Alzheimer’s disease, biomarkers, early diagnosis, healthcare organizational models, mild cognitive impairment, prodromal Alzheimer’s disease, public health

DOI: 10.3233/JAD-190670

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Richards, Emma | Bayer, Antony | Tree, Jeremy | Hanley, Claire | Norris, Jade | Tales, Andrea

Article Type: Research Article

Abstract: In this study, reaction time (RT), intraindividual variability (IIV), and errors, and the effects of practice and processing load upon such function, were compared in patients with subcortical ischemic vascular cognitive impairment (SIVCI) [n  = 27] and cognitively healthy older adults (CH) [n  = 26]. Compared to CH aging, SIVCI was characterized by a profile of significantly slowed RT, raised IIV, and higher error levels, particularly in the presence of distracting stimuli, indicating that the integrity and/or accessibility of the additional functions required to support high processing load, serial search strategies, are reduced in SIVCI. Furthermore, although practice speeded RT in SIVCI, …unlike CH, practice did not lead to an improvement in IIV. This indicates that improvement in RT in SIVCI can in fact mask an abnormally high degree of IIV. Because IIV appears more related to disease, function, and health than RT, its status and potential for change may represent a particularly meaningful, and relevant, disease characteristic of SIVCI. Finally, a high level of within-group variation in the above measures was another characteristic of SIVCI, with such processing heterogeneity in patients with ostensibly the same diagnosis, possibly related to individual variation in pathological load. Detailed measurement of RT, IIV, errors, and practice effects therefore reveal a degree of functional impairment in brain processing not apparent by measuring RT in isolation. Show more

Keywords: Intra-individual variability, methodology, reaction time, subcortical ischemic vascular cognitive impairment

DOI: 10.3233/JAD-190889

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

Authors: Krolak-Salmon, Pierre | Maillet, Audrey | Vanacore, Nicola | Selbaek, Geir | Rejdak, Konrad | Traykov, Latchezar | Politis, Antonios | Georges, Jean | Borson, Soo | Leperre-Desplanques, Armelle

Article Type: Review Article

Abstract: Neurocognitive disorders causing progressive cognitive, functional, and behavioral impairment remain underdiagnosed. The needs for a timely diagnosis are now widely acknowledged since person-centered care helps to preserve life quality and prevent crises. One powerful barrier to detection in primary care is the lack of an easy-to-follow stepwise approach, grounded in evidence and consistent with high-quality specialty practice. To help fill this gap, the current European Joint Action proposes a graduated diagnosis strategy tailored to the patients’ needs and wills, clarifying appropriate components for primary and specialty care. This strategy considers a first evaluation in primary care that may detect a …neurocognitive disorder, that would lead to a second evaluation step allowing etiological diagnosis hypotheses performed mostly by the specialist. A third evaluation stage considering some biological, electrophysiological, or neuroimaging complementary techniques would be proposed to atypical cases or patients willing to consider access to research. Show more

Keywords: Alzheimer’s disease, detection, diagnosis, general practitioner, memory, neurocognitive disorder

DOI: 10.3233/JAD-190461

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

Authors: Goldstein, Felicia C. | Loring, David W. | Thomas, Tiffany | Saleh, Sabria | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: The utility of recognition memory for identifying persons with biomarker evidence of Alzheimer’s disease (AD) is unclear since prior studies of mild cognitive impairment (MCI) relied only on clinical diagnosis and did not include simultaneous measures of central amyloidosis and tauopathy. Objective: We evaluated whether recognition memory and associated indices, including discriminability and response bias from signal detection theory, differentiate persons with amnestic MCI (aMCI) due to prodromal AD from non-prodromal AD. Method: Sixty older adults with aMCI were classified as prodromal AD (n  = 28) or non-prodromal AD (n  = 32) based upon cerebrospinal fluid levels …of amyloid-β and tau. Memory was assessed using the Hopkins Verbal Learning Test-Revised which includes free recall and recognition. Results: ANCOVAs adjusting for age indicated comparable (all p  > 0.05) performances between prodromal and non-prodromal MCI groups respectively on traditional HVLT-R recognition measures of hits (mean±SD: 9.5±3.0 versus 10.9±1.7), false alarms (1.8±1.8 versus 1.5±1.5), and hits minus false alarms (7.7±3.0 versus 9.2±2.6). In contrast, discriminability (d’), which reflects how easily targets and distractors are distinguished, was significantly (p  = 0.009) poorer in the prodromal versus non-prodromal groups (3.1±1.9 versus 4.8±2.0, effect size = 0.87). In addition, only d’ significantly predicted group membership (OR = 0.66, CI = 0.48–0.92, p  = 0.04). Response bias, the tendency to report that a target did or did not appear, was comparable between groups (0.08±1.1 versus –0.04±1.3). Conclusion: Recognition discriminability is significantly poorer in aMCI with biomarker evidence of prodromal AD. In contrast to traditional recognition indices, discriminability from signal detection theory may be superior in identifying aMCI due to AD versus non-AD etiologies. Show more

Keywords: Alzheimer’s disease, amyloid-β , amyloidosis, biomarkers, mild cognitive impairment, prodromal Alzheimer’s disease, recognition memory, signal detection, tau

DOI: 10.3233/JAD-190468

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Nie, Ran | Wu, Zhou | Ni, Junjun | Zeng, Fan | Yu, Weixian | Zhang, Yufeng | Kadowaki, Tomoko | Kashiwazaki, Haruhiko | Teeling, Jessica L. | Zhou, Yanmin

Article Type: Research Article

Abstract: Abnormal accumulation of amyloid-β (Aβ) in the brain is the most significant pathological hallmark of Alzheimer’s disease (AD). We have found that chronic systemic exposure to lipopolysaccharide of Porphyromonas gingivalis (P. gingivalis ) induces the accumulation of Aβ in the brain of middle-aged mice. On the other hand, recent research has shown that circulating Aβ is transferred into the brain; however, the involvement of chronic systemic P. gingivalis infection in the peripheral Aβ metabolism is unknown. We hypothesized that chronic P. gingivalis infection expands Aβ pools in peripheral inflammatory tissues and thereby contributes to the accumulation of …Aβ in the brain of patients with periodontitis. We showed that the increased expression of IL-1β, AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was mainly co-localized with macrophages in the liver of P. gingivalis infected mice. Blocking CatB and NF-κ B significantly inhibited the P. gingivalis- induced expression of IL-1β, AβPP770 , Aβ1-42 , and Aβ3-42 in RAW264.7 cells. Aβ3-42 , but not Aβ1-42 , induced the significant death of macrophages, and the reduction of phagocytic abilities induced by Aβ3-42 tended to be higher than that induced by Aβ1-42 . Additionally, the expression of AβPP770 , CatB, Aβ1-42 , and Aβ3-42 was determined in the macrophages of gingival tissues from periodontitis patients. These findings indicate that chronic systemic P. gingivalis infection induces the Aβ accumulation in inflammatory monocytes/macrophages via the activation of CatB/NF-κ B signaling, thus suggesting monocytes/macrophages serve as a circulating pool of Aβ in patients with periodontitis. Taken together, CatB may be a novel therapeutic target for preventing the periodontitis-related AD initiation and pathological progression. Show more

Keywords: Alzheimer’s disease, Cathepsin B, interleukin 1β, monocytes/macrophages, nuclear factor-kappa B, peripheral amyloid-β, Porphyromonas gingivalis infection, systemic inflammation

DOI: 10.3233/JAD-190298

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Teipel, Stefan J. | Kuper-Smith, Jan O. | Bartels, Claudia | Brosseron, Frederic | Buchmann, Martina | Buerger, Katharina | Catak, Cihan | Janowitz, Daniel | Dechent, Peter | Dobisch, Laura | Ertl-Wagner, Birgit | Fließbach, Klaus | Haynes, John-Dylan | Heneka, Michael T. | Kilimann, Ingo | Laske, Christoph | Li, Siyao | Menne, Felix | Metzger, Coraline D. | Priller, Josef | Pross, Verena | Ramirez, Alfredo | Scheffler, Klaus | Schneider, Anja | Spottke, Annika | Spruth, Eike J. | Wagner, Michael | Wiltfang, Jens | Wolfsgruber, Steffen | Düzel, Emrah | Jessen, Frank | Dyrba, Martin | the DELCODE study group

Article Type: Research Article

Abstract: Diffusion changes as determined by diffusion tensor imaging are potential indicators of microstructural lesions in people with mild cognitive impairment (MCI), prodromal Alzheimer’s disease (AD), and AD dementia. Here we extended the scope of analysis toward subjective cognitive complaints as a pre-MCI at risk stage of AD. In a cohort of 271 participants of the prospective DELCODE study, including 93 healthy controls and 98 subjective cognitive decline (SCD), 45 MCI, and 35 AD dementia cases, we found reductions of fiber tract integrity in limbic and association fiber tracts in MCI and AD dementia compared with controls in a tract-based analysis …(p  < 0.05, family wise error corrected). In contrast, people with SCD showed spatially restricted white matter alterations only for the mode of anisotropy and only at an uncorrected level of significance. DTI parameters yielded a high cross-validated diagnostic accuracy of almost 80% for the clinical diagnosis of MCI and the discrimination of Aβ positive MCI cases from Aβ negative controls. In contrast, DTI parameters reached only random level accuracy for the discrimination between Aβ positive SCD and control cases from Aβ negative controls. These findings suggest that in prodromal stages of AD, such as in Aβ positive MCI, multicenter DTI with prospectively harmonized acquisition parameters yields diagnostic accuracy meeting the criteria for a useful biomarker. In contrast, automated tract-based analysis of DTI parameters is not useful for the identification of preclinical AD, including Aβ positive SCD and control cases. Show more

Keywords: amyloid, anisotropy, cerebral white matter, cognition, diagnosis, diffusion tensor imaging, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-190446

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

Authors: La Rosa, Francesca | Saresella, Marina | Marventano, Ivana | Piancone, Federica | Ripamonti, Enrico | Al-Daghri, Nasser | Bazzini, Chiara | Paola Zoia, Chiara | Conti, Elisa | Ferrarese, Carlo | Clerici, Mario

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is associated with the accumulation of amyloid-β (Aβ ) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. Objective: We utilized an in vitro model reproducing the Aβ -driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aβ -mediated inflammasome activation and the ability of macrophages to eliminate Aβ via phagocytosis and autophagy. Methods: THP-1-derived macrophages were stimulated in vitro with Aβ 42 …or with Aβ 42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. Results: IL-1β , IL-18, and caspase-1 were increased whereas Aβ phagocytosis and TREM2 were reduced in LPS+Aβ 42 -stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1β production and TREM2 expression. Notably, whereas D4T reduced Aβ phagocytosis, Aβ autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. Conclusion: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aβ autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario. Show more

Keywords: Alzheimer’s disease, amyloid-β phagocytosis, autophagy, cytokines, D4T, NLRP3-inflammasome, 0000-0003-3181-9505

DOI: 10.3233/JAD-181259

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

Authors: Chen, Guanqun | Yang, Kun | Du, Wenying | Hu, Xiaochen | Han, Ying

Article Type: Research Article

Abstract: Background: Subjective cognitive decline (SCD) refers to the self-perception of cognitive decline among cognitively normal elderly individuals. SCD related worry confers a higher risk of developing cognitive decline. However, the clinical characteristics of SCD patients with worry are not clear. Objective: To explore the clinical characteristics of SCD patients with worry. Methods: A cross-sectional study was carried out, with 270 consecutive participants of the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Participants were classified as normal controls (n  = 36), SCD patients without worry (n  = 91), or SCD patients with worry (n  = 143) and were comprehensively …compared on 1) their self-perception of cognitive decline, 2) multiple cognitive domains, 3) neuropsychiatric symptoms, and 4) sleep status. Results: SCD patients with worry had significantly more self-perception of cognitive decline (p  <  0.001); increased depression (p  <  0.001) and anxiety (p  <  0.001); decreased sleep quality (p  <  0.001), sleep latency (p  <  0.05), sleep time (p  <  0.01), and sleep efficiency (p  <  0.05); more sleep disorders (p  <  0.05) and daytime dysfunction (p  <  0.05); and a higher global score on the Pittsburgh Sleep Quality Index (p  <  0.001) than normal controls. Although there was a significant increase only in self-perception of cognitive decline (p  <  0.001), anxiety (p  <  0.001), and Pittsburgh Sleep Quality Index scores (p  <  0.05), the severity of the increase in those without worry was between that in SCD patients with worry and normal controls. Conclusion: Our findings show that participants who had SCD with worry showed distinct clinical characteristics compared with normal controls and SCD patients without worry, which could be useful for understanding the higher risk in SCD patients with worry of subsequently developing Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, clinical characteristic, neuropsychiatric symptoms, prevention trials, sleep disorders, subjective cognitive decline, subjective cognitive decline questionnaire

DOI: 10.3233/JAD-190501

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

Authors: Liu, Xiaoguang | Hebron, Michaeline L. | Mulki, Sanjana | Wang, Chen | Lekah, Elizabeth | Ferrante, Dalila | Shi, Wangke | Kurd-Misto, Bahjat | Moussa, Charbel

Article Type: Research Article

Abstract: Ubiquitin Specific Protease-13 (USP13) is a de-ubiquinating enzyme that regulates protein ubiquitination and clearance. The role of USP13 is largely unknown in neurodegeneration. In this study we aim to demonstrate whether tau accumulation and/or clearance depends on ubiquitination/de-ubiquitination via USP-13. We used transgenic animal models of human amyloid precursor protein (APP) or P301L tau mutations and genetically knocked-down USP13 expression via shRNA to determine USP13 effects on tau ubiquitination and levels. We found a two-fold increase of USP13 levels in postmortem Alzheimer’s disease (AD) brains. USP13 knockdown significantly increased the activity of the 20S proteasome and reduced the levels of …hyper-phosphorylated tau (p-tau) in primary cortical neurons. USP13 knockdown also reduced the levels of amyloid and increased p-tau ubiquitination and clearance in transgenic animal models that overexpress murine tau as a result of the expression of familial APP mutations (TgAPP) and the human mutant P301L tau (rTg4510), respectively. Clearance of p-tau appears to be mediated by autophagy in these animal models. Taken together, these data suggest that USP13 knockdown reduces p-tau accumulation via regulation of ubiquitination/de-ubiquitination and mediates its clearance via autophagy and/or the proteasome. These results suggest that USP13 inhibition may be a therapeutic strategy to reduce accumulation of plaques and toxic p-tau in AD and human tauopathies. Show more

Keywords: Alzheimer’s disease, amyloid, tau, ubiquitin, USP13

DOI: 10.3233/JAD-190635

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

Authors: Jiang, Juanjuan | Yan, Zhuangzhi | Sheng, Can | Wang, Min | Guan, Qinglan | Yu, Zhihua | Han, Ying | Jiang, Jiehui

Article Type: Research Article

Abstract: Background: Detecting subtle changes in visual attention from electroencephalography (EEG) and the perspective of eye movement in mild cognitive impairment (MCI) patients can be of great significance in screening early Alzheimer’s disease (AD) in a large population at primary care. Objective: We proposed an automatic, non-invasive, and quick MCI detection approach based on multimodal physiological signals for clinical decision-marking. Methods: The proposed model recruited 152 patients with MCI and 184 healthy elderly controls (HC) who underwent EEG and eye movement signal recording under a visual stimuli task, as well as other neuropsychological assessments. Forty features were …extracted from EEG and eye movement signals by linear and nonlinear analysis. The features related to MCI were selected by logistic regression analysis. To evaluate the efficacy of this MCI detection approach, we applied the same procedures to achieve the Clinical model, EEG model, Eye movement model, EEG+ Clinical model, Eye movement+ Clinical model, and Combined model, and compared the classification accuracy between the MCI and HC groups with the above six models. Results: After the penalization of logistic regression analysis, five features from EEG and eye movement features exhibited significant differences (p  <  0.05). In the classification experiment, the combined model resulted in the best accuracy. The average accuracy for the Clinical/EEG/Eye movement/EEG+ Clinical/Eye movement+ Clinical/Combined model was 68.69%, 61.79%, 73.13%, 69.46%, 75.61%, and 81.51%, respectively. Conclusion: These results suggest that the proposed MCI detection tool has the potential to screen MCI patients from HCs and may be a powerful tool for personalized precision MCI screening in the large-scale population under primary care condition. Show more

Keywords: Attention, electroencephalography, eye movement, mild cognitive impairment, multimodal detection, 2017LCSY345

DOI: 10.3233/JAD-190628

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

Authors: Kang, David E. | Woo, Jung A.

Article Type: Review Article

Abstract:  The defining pathological hallmarks of Alzheimer’s disease (AD) are proteinopathies marked by the amyloid-β (Aβ) peptide and hyperphosphorylated tau. In addition, Hirano bodies and cofilin-actin rods are extensively found in AD brains, both of which are associated with the actin cytoskeleton. The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis. In this review, we discuss the regulation of cofilin by multiple signaling events impinging on LIM kinase-1 (LIMK1) and/or Slingshot homolog-1 (SSH1) downstream of Aβ. Such pathophysiological signaling pathways impact actin dynamics to regulate synaptic …integrity, mitochondrial translocation of cofilin to promote neurotoxicity, and formation of cofilin-actin pathology. Other intracellular signaling proteins, such as β-arrestin, RanBP9, Chronophin, PLD1, and 14-3-3 also impinge on the regulation of cofilin downstream of Aβ. Finally, we discuss the role of activated cofilin as a bridge between actin and microtubule dynamics by displacing tau from microtubules, thereby destabilizing tau-induced microtubule assembly, missorting tau, and promoting tauopathy. Show more

Keywords: Alzheimer’s disease, amyloid, β-arrestin, chronophin, cofilin, cytoskeleton, F-actin, LIMK1, microtubule, mitochondria, PLD1, slingshot, SSH1, tau

DOI: 10.3233/JAD-190585

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

Authors: Zou, Shengzhen | Zhang, Jie | for Alzheimer’s Disease Neuroimaging Initiative | Chen, Wei

Article Type: Research Article

Abstract: Apolipoproteins (APOs) have been implicated in the pathogenesis of Alzheimer’s disease (AD). In the present study, we aimed to investigate if patterns of cerebrospinal fluid (CSF) APOs (APOA-I, APOC-III, APOD, APOE, APOH, and APOJ) levels are associated with changes over time in cognition, memory performance, neuroimaging markers, and AD-related pathologies (CSF Aβ42 , t-tau, and p-tau) in non-demented older adults. At baseline, a total of 241 non-demented older adults with CSF APOs data was included in the present analysis. Hierarchical agglomerative cluster analysis including the six CSF APOs was carried out. Among non-demented older adults, we identified two clusters. Compare …with the first cluster, the second cluster had higher levels of APOs in CSF. Additionally, the second cluster showed a more benign disease course, including slower cognitive decline and slower p-tau accumulation in CSF. Our data highlight the importance of APOs in the pathogenesis of AD. Show more

Keywords: Alzheimer’s disease, apolipoproteins, cluster analysis, cognitive decline

DOI: 10.3233/JAD-190314

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

Authors: Paley, Elena L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD)-associated sequence (ADAS) of cultured fecal bacteria was discovered in human gut targeted screening. This study provides important information to expand our current understanding of the structure/activity relationship of ADAS and putative inhibitors/activators that are potentially involved in ADAS appearance/disappearance. The NCBI database analysis revealed that ADAS presents at a large proportion in American Indian Oklahoman (C&A) with a high prevalence of obesity/diabetes and in colorectal cancer (CRC) patients from the US and China. An Oklahoman non-native group (NNI) showed no ADAS. Comparison of two large US populations reveals that ADAS is more frequent in individuals aged ≥66 …and in females. Prevalence and levels of fecal metabolites are altered in the C&A and CRC groups versus controls. Biogenic amines (histamine, tryptamine, tyramine, phenylethylamine, cadaverine, putrescine, agmatine, spermidine) that present in food and are produced by gut microbiota are significantly higher in C&A (e.g., histamine/histidine 95-fold) versus NNI (histamine/histidine 16-fold). The majority of these bio-amines are cytotoxic at concentrations found in food. Inositol phosphate signaling implicated in AD is altered in C&A and CRC. Tryptamine stimulated accumulation of inositol phosphate. The seizure-eliciting tryptamine induced cytoplasmic vacuolization and vesiculation with cell fragmentation. Present additions of ADAS-carriers at different ages including infants led to an ADAS-comprising human sample size of 2,830 from 27 studies from four continents (North America, Australia, Asia, Europe). Levels of food-derived monoamine oxidase inhibitors and anti-bacterial compounds, the potential modulators of ADAS-bacteria growth and biogenic amine production, were altered in C&A versus NNI. ADAS is attributable to potentially modifiable risk factors of AD associated diseases. Show more

Keywords: Alzheimer’s human gut metagenome, angiogenesis, biogenic amines, food, gut metabolomics, protein biosynthesis

DOI: 10.3233/JAD-190873

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-37, 2019

Authors: Morsy, Ahmed | Trippier, Paul C.

Article Type: Review Article

Abstract: No cure or disease-modifying therapy for Alzheimer’s disease (AD) has yet been realized. However, a multitude of pharmacological targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathological hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N -methyl-D -aspartate receptor blockade treatments that are clinically approved …for the symptomatic treatment of AD. Additional targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of ‘sensitive targets’ that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target’s function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our analysis to targets that have emerged in the last decade and targets that have been validated using small molecules in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and critical targets suitable for small molecule drug intervention. Show more

Keywords: Alzheimer’s disease, amyloid, drug discovery, therapeutics, toxicity

DOI: 10.3233/JAD-190744

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-32, 2019

Authors: Toppala, Sini | Ekblad, Laura L. | Lötjönen, Jyrki | Helin, Semi | Hurme, Saija | Johansson, Jarkko | Jula, Antti | Karrasch, Mira | Koikkalainen, Juha | Laine, Hanna | Parkkola, Riitta | Viitanen, Matti | Rinne, Juha O.

Article Type: Research Article

Abstract: Background: Type 2 diabetes (T2DM) increases the risk for Alzheimer’s disease (AD) but not for AD neuropathology. The association between T2DM and AD is assumed to be mediated through vascular mechanisms. However, insulin resistance (IR), the hallmark of T2DM, has been shown to associate with AD neuropathology and cognitive decline. Objective: To evaluate if midlife IR predicts late-life cognitive performance and cerebrovascular lesions (white matter hyperintensities and total vascular burden), and whether cerebrovascular lesions and brain amyloid load are associated with cognitive functioning. Methods: This exposure-to-control follow-up study examined 60 volunteers without dementia (mean age 70.9 …years) with neurocognitive testing, brain 3T-MRI and amyloid-PET imaging. The volunteers were recruited from the Finnish Health 2000 survey (n  = 6062) to attend follow-up examinations in 2014–2016 according to their insulin sensitivity in 2000 and their APOE genotype. The exposure group (n  = 30) had IR in 2000 and the 30 controls had normal insulin sensitivity. There were 15 APOE ɛ 4 carriers per group. Statistical analyses were performed with multivariable linear models. Results: At follow-up the IR+group performed worse on executive functions (p  = 0.02) and processing speed (p  = 0.007) than the IR- group. The groups did not differ in cerebrovascular lesions. No associations were found between cerebrovascular lesions and neurocognitive test scores. Brain amyloid deposition associated with slower processing speed. Conclusion: Midlife IR predicted poorer executive functions and slower processing speed, but not cerebrovascular lesions. Brain amyloid deposition was associated with slower processing speed. The association between midlife IR and late-life cognition might not be mediated through cerebrovascular lesions measured here. Show more

Keywords: Alzheimer’s disease, amyloid, APOE , 11C-PIB, cerebrovascular lesions, cognition, follow-up study, insulin resistance, magnetic resonance imaging, PET scan

DOI: 10.3233/JAD-190691

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

Authors: Smeijer, David | Ikram, M. Kamran | Hilal, Saima

Article Type: Research Article

Abstract: Perivascular compartments surrounding the penetrating arteries in the brain are part of a physiologic system, which facilitates fluids exchange and clearance of solutes from the brain. The perivascular compartments become visible on MRI when enlarged and are commonly referred to as perivascular spaces (ePVS). Previous studies on the association between ePVS and dementia have been inconsistent due to varying methods of measuring ePVS. As a frame of reference for future MRI studies on ePVS, we systematically review the literature on ePVS as a marker of vascular brain injury related to dementia from population-based as well as hospital-based settings. We identified …three longitudinal and ten cross-sectional studies involving 7,744 persons. Potential outcomes were all-cause dementia, Alzheimer’s disease, and vascular dementia. There was considerable heterogeneity in ePVS assessment: with studies using either visual inspection or segmentation, examining different brain locations and implementing different grading scales. Moreover, out of the total of 13 studies, all five studies on vascular dementia reported an association with presence of basal ganglia ePVS after adjustment for age, gender, and white matter hyperintensities. For seven studies on Alzheimer’s disease and all-cause dementia, the results were ambiguous. This review did not identify an independent association of ePVS with prevalent or incident dementia. Harmonized methods for ePVS assessment, tested across different populations, may benefit future MRI studies on ePVS and dementia. Show more

Keywords: Cerebral small vessel disease, dementia, enlarged perivascular spaces, magnetic resonance imaging

DOI: 10.3233/JAD-190527

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

Authors: Tsentidou, Glykeria | Moraitou, Despina | Tsolaki, Magda

Article Type: Research Article

Abstract: Cardiovascular health declines with age, due to vascular risk factors, and this leads to an increasing risk of cognitive decline. Mild cognitive impairment (MCI) is defined as the negative cognitive changes beyond what is expected in normal aging. The purpose of the study was to compare older adults with vascular risk factors (VRF), MCI patients, and healthy controls (HC) in main dimensions of cognitive control. The sample comprised a total of 109 adults, aged 50 to 85 (M = 66.09, S.D. = 9.02). They were divided into three groups: 1) older adults with VRF, 2) MCI patients, and 3) healthy controls (HC). VRF and …MCI did not differ significantly in age, educational level, or gender as was the case with HC. The tests used mainly examine inhibition, cognitive flexibility, and working memory processing. Results showed that the VRF group had more Set Loss Errors in drawing designs indicating deficits in establishing cognitive set and in cognitive shifting. MCI patients displayed lower performance in processing. Hence, different types of specific impairments emerge in vascular aging and MCI, and this may imply that discrete underlying pathologies may play a role in the development of somewhat different profiles of cognitive decline. Show more

Keywords: Cardiovascular risk factors, cognitive impairment, inhibitory control, vascular hypothesis of cognitive aging, visuospatial ability, working memory

DOI: 10.3233/JAD-190638

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Wang, Qian | Jiang, Hailun | Wang, Linlin | Yi, Hong | Li, Zhuorong | Liu, Rui

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive impairments. Vitegnoside is a flavonoid present in the medicinal plant Vitex negundo , widely used as a folk medicine in several Asian countries including China. It possesses several biological activities, including axon outgrowth, but no evidence is available on its effect on AD. Since no effective treatment is available to cure AD, the effect of vitegnoside on this disease was investigated. The human neuroblastoma SH-SY5Y cell line carrying the Swedish mutation that induces AβPP overexpression was used as an in vitro AD cell model. AβPP overexpression does …not induce toxicity per se unless triggered by copper. Vitegnoside promoted neuroprotection through the improvement of cell viability, maintenance of cytomembrane integrity and nuclear homogeneity in these cells, but these effects were not observed in the copper-treated SH-SY5Y cells without AβPP overexpression used as the wild-type control, indicating that vitegnoside exerted neuroprotection under copper-triggered Aβ toxic conditions. Vitegnoside failed to decrease AβPP expression, Aβ40/42 levels, and oxidative stress due to copper-induced Aβ toxicity. However, its administration protected the mitochondrial function and restored the imbalance between pro-apoptotic and anti-apoptotic proteins. Additionally, vitegnoside inactivated p38 MAPK/MK2, JNK/c-Jun, and downstream NF-κ B inflammatory transductions. Furthermore, the inactivation of p38 MAPK/JNK signaling contributed to vitegnoside-mediated neuroprotection resulting from pharmacological inhibition of p38 MAPK/JNK and in silico interaction prediction. Our study revealed the neuroprotective effect of vitegnoside and its potential mechanisms against copper-induced Aβ neurotoxicity. These findings highlighted the potential therapeutic effect of vitegnoside against AD progression. Show more

Keywords: Alzheimer’s disease, amyloid-β, apoptosis, mitogen-activated protein kinase, vitegnoside

DOI: 10.3233/JAD-190640

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Hamezah, Hamizah Shahirah | Durani, Lina Wati | Yanagisawa, Daijiro | Ibrahim, Nor Faeizah | Aizat, Wan Mohd | Makpol, Suzana | Wan Ngah, Wan Zurinah | Damanhuri, Hanafi Ahmad | Tooyama, Ikuo

Article Type: Research Article

Abstract: Tocotrienol-rich fraction (TRF) is a mixture of vitamin E analogs derived from palm oil. We previously demonstrated that supplementation with TRF improved cognitive function and modulated amyloid pathology in AβPP/PS1 mice brains. The current study was designed to examine proteomic profiles underlying the therapeutic effect of TRF in the brain. Proteomic analyses were performed on samples of hippocampus, medial prefrontal cortex (mPFC), and striatum using liquid chromatography coupled to Q Exactive HF Orbitrap mass spectrometry. From these analyses, we profiled a total of 5,847 proteins of which 155 proteins were differentially expressed between AβPP/PS1 and wild-type mice. TRF supplementation of …these mice altered the expression of 255 proteins in the hippocampus, mPFC, and striatum. TRF also negatively modulated the expression of amyloid beta A4 protein and receptor-type tyrosine-protein phosphatase alpha protein in the hippocampus. The expression of proteins in metabolic pathways, oxidative phosphorylation, and those involved in Alzheimer’s disease were altered in the brains of AβPP/PS1 mice that received TRF supplementation. Show more

Keywords: Alzheimer’s disease, LC-MS, palm oil, proteomics, tocotrienol

DOI: 10.3233/JAD-181171

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Zyśk, Marlena | Clausen, Fredrik | Aguilar, Ximena | Sehlin, Dag | Syvänen, Stina | Erlandsson, Anna

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with …the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12- and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-β (Aβ ) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced Aβ pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration. Show more

Keywords: Alzheimer’s disease, amyloid-β, inflammation, Morris water maze, neurodegeneration astrocytes, PET, traumatic brain injury

DOI: 10.3233/JAD-190572

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2019

Authors: Robinson, Rebecca L. | Rentz, Dorene M. | Bruemmer, Valerie | Andrews, Jeffrey Scott | Zagar, Anthony | Kim, Yongin | Schwartz, Ronald L. | Ye, Wenyu | Fillit, Howard M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the costliest diseases in the United States. Objective: To describe aspects of real-world patient and caregiver burden in patients with clinician-diagnosed early AD, including mild cognitive impairment (MCI) and mild dementia (MILD) due to AD. Methods: Cross-sectional assessment of GERAS-US, a 36-month cohort study of patients seeking care for early AD. Eligible patients were categorized based on study-defined categories of MCI and MILD and by amyloid positivity [+] or negativity [–] within each severity cohort. Demographic characteristics, health-related outcomes, medical history, and caregiver burden by amyloid status are described. …Results: Of 1,198 patients with clinician-diagnosed early AD, 52% were amyloid[+]. For patients in both cohorts, amyloid[–] was more likely to occur in those with: delayed time to an AD-related diagnosis, higher rates of depression, poorer Bath Assessment of Subjective Quality of Life in Dementia scores, and Hispanic/Latino ethnicity (all p  <  0.05). MILD[–] patients (versus MILD[+]) were more medically complex with greater rates of depression (55.7% versus 40.4%), sleep disorders (34.3% versus 26.5%), and obstructive pulmonary disease (11.8% versus 6.6%); and higher caregiver burden (Zarit Burden Interview) (all p  <  0.05). MILD[+] patients had lower function according to the Functional Activities Questionnaire (p  <  0.001), yet self-assessment of cognitive complaints across multiple measures did not differ by amyloid status in either severity cohort. Conclusions: Considerable patient and caregiver burden was observed in patient’s seeking care for memory concerns. Different patterns emerged when both disease severity and amyloid status were evaluated underscoring the need for further diagnostic assessment and care for patients. Study Registry: H8A-US-B004; ClinicalTrials.gov: NCT02951598. Show more

Keywords: Alzheimer’s disease, amyloid, burden of illness, florbetapir F18, mild Alzheimer’s dementia, mild cognitive impairment

DOI: 10.3233/JAD-190430

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

Authors: Jingami, Naoto | Uemura, Kengo | Asada, Megumi | Kuzuya, Akira | Yamada, Shigeki | Ishikawa, Masatsune | Kawahara, Takashi | Iwasaki, Takuya | Atsuchi, Masamichi | Takahashi, Ryosuke | Kinoshita, Ayae

Article Type: Research Article

Abstract: Background: Extensive research into cerebrospinal fluid (CSF) biomarkers was performed in patients with idiopathic normal pressure hydrocephalus (iNPH). Most prior research into CSF biomarkers has been one-point observation. Objective: To investigate dynamic changes in CSF biomarkers during routine tap test in iNPH patients. Methods: We analyzed CSF concentrations of tau, amyloid-β (Aβ ) 42 and 40, and leucine rich α -2-glycoprotein (LRG) in 88 consecutive potential iNPH patients who received a tap test. We collected two-point lumbar CSF separately at the first 1 ml (First Drip (FD)) and at the last 1 ml (Last Drip (LD)) during …the tap test and 9 patients who went on to receive ventriculo-peritoneal shunt surgery each provided 1 ml of ventricular CSF (VCSF). Results: Tau concentrations were significantly elevated in LD and VCSF compared to FD (LD/FD = 1.22, p  = 0.003, VCSF/FD = 2.76, p  = 0.02). Conversely, Aβ 42 (LD/FD = 0.80, p  <  0.001, VCSF/FD = 0.38, p  = 0.03) and LRG (LD/FD = 0.74, p  <  0.001, VCSF/FD = 0.09, p  = 0.002) concentrations were significantly reduced in LD and VCSF compared to FD. Gait responses to the tap test and changes in cognitive function in response to shunt were closely associated with concentrations of tau (p  = 0.02) and LRG (p  = 0.04), respectively. Conclusions: Dynamic changes were different among the measured CSF biomarkers, suggesting that LD of CSF as sampled during the tap test reflects an aspect of VCSF contributing to the pathophysiology of iNPH and could be used to predict shunt effectiveness. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebrospinal fluid biomarker, idiopathic normal pressure hydrocephalus, leucine rich α-2-glycoprotein, tap test, tau

DOI: 10.3233/JAD-190775

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Sutin, Angelina R. | Stephan, Yannick | Terracciano, Antonio

Article Type: Research Article

Abstract: Personality traits, such as higher Neuroticism and lower Conscientiousness, are associated with risk of Alzheimer’s disease and other dementias. A diagnosis of dementia relies, in part, on informant ratings of the individual’s cognitive status. Here we examine whether self-reported personality traits are associated with four measures of informant-rated cognition up to a decade later. Participants from the Health and Retirement Study (N = 2,536) completed a five-factor model measure of personality in 2006 or 2008. Informants completed the 2016 Harmonized Cognitive Assessment Protocol (HCAP), which included ratings of the participant’s current cognitive functioning and change in cognitive function over the last decade …assessed with the IQCODE, Blessed, 1066, and CSID. Controlling for characteristics of the participant, informant, and their relationship, higher Neuroticism and lower Conscientiousness were associated consistently with worse informant-rated cognition. The association between Openness and better informant-rated cognition was due primarily to higher baseline cognitive function. Extraversion and Agreeableness were associated with better informant-rated cognition only among participants who were cognitively intact at follow-up. The present research suggests that knowledgeable informants are able to detect cognitive deficits associated with personality. Show more

Keywords: Cognitive decline, dementia, five factor model, informant-rated cognition

DOI: 10.3233/JAD-190555

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

Authors: Chou, Ping-Song | Wu, Meng-Ni | Yang, Chen-Cheng | Shen, Cheng-Ting | Yang, Yuan-Han

Article Type: Research Article

Abstract: Background: Shared links between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) have been well-known. A high concentration of advanced glycation end products (AGEs) has been reported to contribute to impaired mobility in patients with AD, but there is limited understanding regarding the longitudinal impact of AGEs on cognitive performance. Objective: This study aims to explore whether the concentrations of AGEs mediate the clinical progression of cognitive performance in patients with AD and T2DM. Methods: Twenty-five patients aged 79.0±5.8 years who were diagnosed with probable AD with a Clinical Dementia Rating (CDR) of 0.5 or …1 and T2DM were enrolled in this study. When patients participated in the study, the concentration of plasma AGEs was tested. A series of neuropsychological tests, namely the Mini-Mental Status Examination (MMSE), Cognitive Assessment Screening Instrument (CASI), and CDR, were performed annually during follow-up. The association between the concentration of AGEs and changes in overall cognition and cognition related daily living performance was analyzed. Results: After the mean 48.6±2.1 months of follow-up, AGEs were found to be significantly associated with a change in CDR. A total of 12 (48% ) patients experienced a decline in CDR; they had a significantly higher concentration of AGEs than did those whose CDR did not deteriorate (100.5 ± 14.2 versus 81.5 ± 17.7; p  = 0.007). This difference in CDR remained significant after adjustment for age, sex, education level, and apolipoprotein E4 status (adjusted p  = 0.020). Conclusion: In conclusion, this study indicates that a high concentration of AGEs may be a predictor of a long-term decline in cognition related daily living performance in patients with AD and T2DM. Show more

Keywords: Advanced glycation end products, Alzheimer’s disease, clinical dementia rating, diabetes mellitus

DOI: 10.3233/JAD-190639

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

Authors: Castora, Frank J. | Conyers, Barbara L. | Gershon, Blake S. | Kerns, Kimberly A. | Campbell, Jr , Robert | Simsek-Duran, Fatma

Article Type: Research Article

Abstract: Mitochondrial dysfunction is recognized as a critical component in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). Deficits in oxidative capacity and, specifically, cytochrome c oxidase (CO) activity have been reported in AD brains and platelets. We previously identified a point mutation at np 9861 in AD brain mitochondrial DNA (mtDNA) that alters amino acid 219 of subunit III of CO from phenylalanine to leucine. We rapidly screened and quantitated levels of T9861C in samples using mismatched PCR-RFLP and nucleotide extension assays. Six of 40 AD brains possessed the T9861C mutation (designated AD + ) compared to zero of 40 …age-matched control brains. The 15% frequency of T9861C in AD brain is 115-fold higher than the frequency (0.13% ) reported in 9,986 human mtDNA samples queried in world-wide databases. T9861C is heteroplasmic, with mutant load varying from 11% to >95% . Detected initially in parietal cortex, T9861C is not localized to that region but is also found in temporal cortex and caudate but not in hippocampus. The mutant load is unequally distributed throughout these brain regions with the highest load occurring in the parietal or temporal cortex. CO activity normalized to citrate synthase (CS) is reduced an average of 48.5% in AD + brains. CO/CS ratios amongst controls and the two AD populations (AD and AD+) were significantly different (p  = 0.001). Post hoc differences were also significant between controls and AD + (p  = 0.001) and controls and AD (p  = 0.019). There was no significant difference between AD and AD + (p  = 0.317). Show more

Keywords: Alzheimer’s disease, cytochrome oxidase subunit III, DNA, DNA mutational analysis, mitochondrial

DOI: 10.3233/JAD-190176

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

Authors: Amlie-Wolf, Alexandre | Tang, Mitchell | Way, Jessica | Dombroski, Beth | Jiang, Ming | Vrettos, Nicholas | Chou, Yi-Fan | Zhao, Yi | Kuzma, Amanda | Mlynarski, Elisabeth E. | Leung, Yuk Yee | Brown, Christopher D. | Wang, Li-San | Schellenberg, Gerard D.

Article Type: Research Article

Abstract: Most of the loci identified by genome-wide association studies (GWAS) for late-onset Alzheimer’s disease (LOAD) are in strong linkage disequilibrium (LD) with nearby variants all of which could be the actual functional variants, often in non-protein-coding regions and implicating underlying gene regulatory mechanisms. We set out to characterize the causal variants, regulatory mechanisms, tissue contexts, and target genes underlying these associations. We applied our INFERNO algorithm to the top 19 non-APOE loci from the IGAP GWAS study. INFERNO annotated all LD-expanded variants at each locus with tissue-specific regulatory activity. Bayesian co-localization analysis of summary statistics and eQTL data was performed …to identify tissue-specific target genes. INFERNO identified enhancer dysregulation in all 19 tag regions analyzed, significant enrichments of enhancer overlaps in the immune-related blood category, and co-localized eQTL signals overlapping enhancers from the matching tissue class in ten regions (ABCA7, BIN1, CASS4, CD2AP, CD33, CELF1, CLU, EPHA1, FERMT2, ZCWPW1 ). In several cases, we identified dysregulation of long noncoding RNA (lncRNA) transcripts and applied the lncRNA target identification algorithm from INFERNO to characterize their downstream biological effects. We also validated the allele-specific effects of several variants on enhancer function using luciferase expression assays. By integrating functional genomics with GWAS signals, our analysis yielded insights into the regulatory mechanisms, tissue contexts, genes, and biological processes affected by noncoding genetic variation associated with LOAD risk. Show more

Keywords: Alzheimer’s disease, bioinformatics, genetics, genomics, long noncoding RNA

DOI: 10.3233/JAD-190568

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2019

Authors: Rajan, Kumar B. | McAninch, Elizabeth A. | Wilson, Robert S. | Weuve, Jennifer | Barnes, Lisa L. | Evans, Denis A.

Article Type: Research Article

Abstract: Background: The association of the APOE ɛ 4 allele with incident Alzheimer’s dementia is higher among European Americans (EAs) than African Americans (AAs), but similar for the rate of cognitive decline. Objective: To examine the racial differences in the association of the APOE ɛ 4 allele with incident Alzheimer’s dementia and cognitive decline. Methods: Using a population-based sample of 5,117 older adults (66% AAs and 63% females), we identified cognitive trajectory groups from a latent class mixed model and examined the association of the APOE ɛ 4 allele with these groups. …Results: The frequency of the APOE ɛ 4 allele was higher among AAs than EAs (37% versus 26%). Four cognitive trajectories were identified: slow, mild, moderate, and rapid. Overall, AAs had a lower baseline global cognition than EAs, and a higher proportion had rapid (7% versus 5%) and moderate (20% versus 15%) decline, but similar mild (44% versus 46%), and lesser slow (29% versus 34%) decline compared to EAs. Additionally, 25% of AAs (13% of EAs) with mild and 5% (<1% of EAs) with slow decline were diagnosed with incident Alzheimer’s dementia. The APOE ɛ 4 allele was associated with higher odds of rapid and moderate decline compared to slow decline among AAs and EAs, but not with mild decline. Conclusions: AAs had lower cognitive levels and were more likely to meet the cognitive threshold for Alzheimer’s dementia among mild and slow decliners, explaining the attenuated association of the ɛ 4 allele with incident Alzheimer’s dementia among AAs. Show more

Keywords: Apolipoproteins E, Alzheimer’s disease, cognitive aging, race relations

DOI: 10.3233/JAD-190538

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Cao, Qin | Meng, Tian | Man, Jianhui | Peng, Dong | Chen, Hongxia | Xiang, Qi | Su, Zhijian | Zhang, Qihao | Huang, Yadong

Article Type: Research Article

Abstract: Glycogen synthase kinase 3β (GSK3β) is a key component of pathogenesis in Alzheimer’s disease, and its inhibitors can restore cognitive function as therapeutic interventions in neurodegenerative diseases. The previous studies showed that acidic fibroblast growth factor (aFGF) could increase the phosphorylation of GSK3β through the PI3K/Akt signaling pathway. We found that aFGF14–154 markedly increased the average length of neurites in neurons damaged by amyloid-β (Aβ), and this promoting effect was blocked by GSK3β inhibitor. It is still unknown which downstream substrates of GSK3β are related to the neurite growth facilitated by aFGF14-154 . The downstream substrates interacting with GSK3β …were screened by co-immunoprecipitation and LTQ-Orbitrap proteomics technology in our study. Collapsin response mediator protein 2 (CRMP2) has been identified as a protein interacting with GSK3β, which is involved in the axon formation and neuron regeneration by regulating microtubule reorganization. aFGF14-154 increased the phosphorylation of GSK3β (Ser9) to inhibit its activity, then was followed by a low phosphorylation level of CRMP2 (Thr514), which led to the neurite growth. The knockdown of CRMP2 blocked the rescue of aFGF14–154 with broken neurites and shrunken cell bodies in neurons with Aβ injury. These results highlight the important role of CRMP2 and its phosphorylation through GSK3β in the effect that aFGF14-154 promoted the growth of neurite damaged by Aβ. Show more

Keywords: Acidic fibroblast growth factor14-154, collapsin response mediator protein 2, glycogen synthase kinase 3β, neurons, CRMP2

DOI: 10.3233/JAD-190458

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

Authors: Snowden, Stuart G. | Ebshiana, Amera A. | Hye, Abdul | Pletnikova, Olga | O’Brien, Richard | Yang, An | Troncoso, Juan | Legido-Quigley, Cristina | Thambisetty, Madhav

Article Type: Research Article

Abstract: Background: Cholinesterase inhibitors represent three of the four treatments for Alzheimer’s disease (AD), and target the pathological reduction of acetylcholine levels. Here we aimed to study the role of other neurotransmitter pathways in AD pathology. Objective: This study aimed to determine associations between AD pathology at both symptomatic and asymptomatic stages of disease progression, and the metabolism of a range of non-cholinergic neurotransmitters. Methods: Tissue samples were obtained from three groups, controls, AD, and ‘asymptomatic AD’ (ASYMAD), i.e., cognitively normal individuals that had significant AD neuropathology. Three brain areas were studied, the middle frontal gyrus (MFG), …the inferior temporal gyrus (ITG), and the cerebellum. Results: 12 of 15 metabolites involved in neurotransmitter metabolism were shown to be associated with AD pathology. Decreases in dopamine were most pronounced in the MFG with lower levels seen in the ASYMAD group compared to control (FC = 0.78, p  = 2.9×10–2 ). In the ITG significant changes were seen in GABAergic and serotonin metabolism between control and AD patients; however, these changes were not seen between control and ASYMAD individuals. Conclusion: These results indicate that dopamine could be depleted in brains with AD pathology but intact cognition, while an imbalance of several neurotransmitters is evident in the brains of AD patients. Show more

Keywords: Asymptomatic Alzheimer’s disease, brain, metabolomics, neurotransmitters

DOI: 10.3233/JAD-190577

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Pozueta, Ana | Lage, Carmen | Martínez, María García | Kazimierczak, Martha | Bravo, María | López-García, Sara | Riancho, Javier | González-Suarez, Andrea | Vázquez-Higuera, José Luis | de Arcocha-Torres, María | Banzo, Ignacio | Bonilla, Julio Jimenez | Berciano, José | Rodríguez-Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Research Article

Abstract: Background: Semantic dementia (SD) is a subtype of frontotemporal lobe degeneration characterized by semantic loss, with other cognitive functions initially preserved. SD requires differential diagnosis with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Semantic knowledge can be evaluated through different tests; however, most of them depend on language. Objective: We describe the development of a brief drawing task that may the helpful for the differential diagnosis of SD. Methods: Seventy-two patients, including 32 AD, 19 bvFTD, and 21 SD were asked to draw 12 items with different age of acquisition and familiarity, belonging to …four different semantic categories. We employed the drawings of healthy volunteers to build a scoring scheme. Results: Turtle, strawberry, train, and envelope were the items of each category that best discriminated between groups and were selected for the Brief drawing task. The discriminatory power of the Brief drawing task between SD versus AD and bvFTD patients, estimated through the area under the curve was 0.84 (95% CI = 0.72–0.96, p  = 0.000007). In a logistic model, the Brief drawing task (p  = 0.003) and VOSP “number location” subtest (p  = 0.016) were significant predictors of the diagnosis of SD versus AD and bvFTD after adjustment by the main covariates. The Brief drawing task provided clinically useful qualitative information. SD drawings were characterized by loss of the distinctive features, intrusions, tendency to prototype, and answers like “I don’t know what this is”. Conclusion: The Brief drawing task appears to reveal deficits in semantic knowledge among patients with SD that may assist in the differential diagnosis with other neurodegenerative diseases. Show more

Keywords: Dementia, differential diagnosis, drawings, semantic dementia, semantic knowledge

DOI: 10.3233/JAD-190660

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

Authors: Jääskeläinen, Olli | Solje, Eino | Hall, Anette | Katisko, Kasper | Korhonen, Ville | Tiainen, Mika | Kangas, Antti J. | Helisalmi, Seppo | Pikkarainen, Maria | Koivisto, Anne | Hartikainen, Päivi | Hiltunen, Mikko | Ala-Korpela, Mika | Soininen, Hilkka | Soininen, Pasi | Haapasalo, Annakaisa | Remes, Anne M. | Herukka, Sanna-Kaisa

Article Type: Research Article

Abstract:  Decreased levels of serum high-density lipoprotein (HDL) cholesterol have previously been linked to systemic inflammation and neurodegenerative diseases, such as Alzheimer’s disease. Here, we aimed to analyze the lipoprotein profile and inflammatory indicators, the high-sensitivity C-reactive peptide (hs-CRP) and glycoprotein acetyls (GlycA), in sporadic and C9orf72 repeat expansion-associated frontotemporal lobar degeneration (FTLD) patients. The C9orf72 hexanucleotide repeat expansion is the most frequent genetic etiology underlying FTLD. The concentrations of different lipid measures in the sera of 67 FTLD patients (15 C9orf72 repeat expansion carriers), including GlycA, were analyzed by nuclear magnetic resonance spectroscopy. To verify the state …of systemic inflammation, hs-CRP was also quantified from patient sera. We found that the total serum HDL concentration was decreased in C9orf72 repeat expansion carriers when compared to non-carriers. Moreover, decreased concentrations of HDL particles of different sizes and subclass were consistently observed. No differences were detected in the very low- and low-density lipoprotein subclasses between the C9orf72 repeat expansion carriers and non-carriers. Furthermore, hs-CRP and GlycA levels did not differ between the C9orf72 repeat expansion carriers and non-carriers. In conclusion, the HDL-related changes were linked with C9orf72 repeat expansion associated FTLD but were not seen to associate with systemic inflammation. The underlying reason for the HDL changes remains unclear. Show more

Keywords: C9orf72 protein, cholesterol, frontotemporal dementia, frontotemporal lobar degeneration, inflammation, lipoproteins

DOI: 10.3233/JAD-190132

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

Authors: Wang, Yiran | Wang, Ying | Bharti, Veni | Zhou, Hong | Hoi, Vanessa | Tan, Hua | Wu, Zijian | Nagakannan, Pandian | Eftekharpour, Eftekhar | Wang, Jun-Feng

Article Type: Research Article

Abstract: Oxidative stress has been hypothesized to play a role in the pathophysiology of Alzheimer’s disease (AD). Previously, we found that total nitrosylated protein levels were increased in the brain of amyloid-β protein precursor (AβPP) and presenilin 1 (PS1) double transgenic mice, an animal model for AD, suggesting that cysteine oxidative protein modification may contribute to this disease. Thioredoxin (Trx) is a major oxidoreductase that can reverse cysteine oxidative modifications such as sulfenylation and nitrosylation, and inhibit oxidative stress. Thioredoxin-interacting protein (Txnip) is an endogenous Trx inhibitor. To understand the involvement of Trx and Txnip in AD development, we investigated Trx …and Txnip in the brain of AβPP/PS1 mice. Using immunoblotting analysis, we found that although Trx protein levels were not changed, Txnip protein levels were significantly increased in hippocampus and frontal cortex of 9- and 12-month-old AβPP/PS1 mice when compared to wild-type mice. Txnip protein levels were also increased by amyloid-β treatment in primary cultured mouse cerebral cortical neurons and HT22 mouse hippocampal cells. Using biotin switch and dimedone conjugation methods, we found that amyloid-β treatment increased protein nitrosylation and sulfenylation in HT22 cells. We also found that downregulation of Txnip, using CRISPR/Cas9 method in HT22 cells, attenuated amyloid-β-induced protein nitrosylation and sulfenylation. Our findings suggest that amyloid-β may increase Txnip levels, subsequently inhibiting Trx reducing capability and enhancing protein cysteine oxidative modification. Our findings also indicate that Txnip may be a potential target for the treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , nitrosylation, oxidative stress, sulfenylation, thioredoxin, thioredoxin-interacting protein

DOI: 10.3233/JAD-190223

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