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

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Low Dose Brain Irradiation Reduces Amyloid-β and Tau in 3xTg-AD Mice

Article Type: Short Communication

Abstract: We have previously reported that low doses of external beam ionizing irradiation reduced amyloid-β (Aβ) plaques and improved cognition in APP/PS1 mice. In this study we investigated the effects of radiation in an age-matched series of 3xTg-AD mice. Mice were hemibrain-irradiated with 5 fractions of 2 Gy and sacrificed 8 weeks after the end of treatment. Aβ and tau were assessed using immunohistochemistry and quantified using image analysis with Definiens Tissue Studio. We observed a significant reduction in Aβ plaque burden and tau staining; these two parameters were significantly correlated. This preliminary data is further support that low doses of radiation …may be beneficial in Alzheimer’s disease. Show more

Keywords: Amyloid-β, radiation, reduction, tau

DOI: 10.3233/JAD-200030

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Price: EUR 27.50

Development of Alzheimer’s Disease after Myocardial Infarction

Authors: Li, Naiyan | Wang, Gang | Lu, Huarong

Article Type: Research Article

Abstract: Many cardiovascular disorders are predisposing factors for Alzheimer’s disease (AD), but the effects of early myocardial infarction (MI) on future development of AD are not well determined. Here, we performed MI on two different AD models in mice, APP/PS1 and rTg4510, which mimicked the plaque formation by amyloid-β peptide aggregates (Aβ) and neurofibrillary tangle formation by phosphorylated Tau (pTau), respectively. In both strains, we detected increased deposit of Aβ or formation of pTau, increased loss of neurons, and poorer performance in behavior tests including a Morris water maze test for spatial reference memory and a locomotion test for motor activity …in mice that had received MI, compared to mice that had been sham operated. Moreover, in a cohort of selected patients, we found that patients with previous MI had more chances to develop AD in the future. Together, our data suggest that the chances to develop AD may increase after MI. Show more

Keywords: Key words: Alzheimer’s disease, amyloid-β peptide aggregates, myocardial infarction, phosphorylated tau

DOI: 10.3233/JAD-200068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Price: EUR 27.50

Transplantation of GABAergic Interneuron Progenitor Attenuates Cognitive Deficits of Alzheimer’s Disease Model Mice

Article Type: Research Article

Abstract: Excitatory (E) and inhibitory (I) balance of neural network activity is essential for normal brain function and of particular importance to memory. Disturbance of E/I balance contributes to various neurological disorders. The appearance of neural hyperexcitability in Alzheimer’s disease (AD) is even suggested as one of predictors of accelerated cognitive decline. In this study, we found that GAD67+ , Parvalbumin+ , Calretinin+ , and Neuropeptide Y+ interneurons were progressively lost in the brain of APP/PS1 mice. Transplanted embryonic medial ganglionic eminence derived interneuron progenitors (IPs) survived, migrated, and differentiated into GABAergic interneuron subtypes successfully at 2 months after transplantation. Transplantation …of IPs hippocampally rescued impaired synaptic plasticity and cognitive deficits of APP/PS1 transgenic mice, concomitant with a suppression of neural hyperexcitability, whereas transplantation of IPs failed to attenuate amyloid-β accumulation, neuroinflammation, and synaptic loss of APP/PS1 transgenic mice. These observations indicate that transplantation of IPs improves learning and memory of APP/PS1 transgenic mice via suppressing neural hyperexcitability. This study highlights a causal contribution of GABAergic dysfunction to AD pathogenesis and the potentiality of IP transplantation in AD therapy. Show more

Keywords: Alzheimer’s disease, cell transplantation, GABA, hyperexcitability, interneuron, interneuron progenitor

DOI: 10.3233/JAD-200010

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Price: EUR 27.50

Clinical and Bacterial Markers of Periodontitis and Their Association with Incident All-Cause and Alzheimer’s Disease Dementia in a Large National Survey

Article Type: Research Article

Abstract: Microbial agents including periodontal pathogens have recently appeared as important actors in Alzheimer’s disease (AD) pathology. We examined associations of clinical periodontal and bacterial parameters with incident all-cause and AD dementia as well as AD mortality among US middle-aged and older adults. Clinical [Attachment Loss (AL); probing pocket depth (PPD)] and bacterial [pathogen immunoglobulin G (IgG)] periodontal markers were investigated in relation to AD and all-cause dementia incidence and to AD mortality, using data from the third National Health and Nutrition Examination Surveys (NHANES III, 1988–1994) linked longitudinally with National Death Index and Medicare data through January 1, 2014, with …up to 26 years of follow-up. Sex- and age-specific multivariable-adjusted Cox proportional hazards models were conducted. Among those ≥65 years, AD incidence and mortality were consistently associated with PPD, two factors and one cluster comprised of IgG titers against Porphyromonas gingivalis (P. gingivalis ), Prevotella melaninogenica (P. melaninogenica ) and Campylobacter rectus (C. rectus ) among others. Specifically, AD incidence was linked to a composite of C. rectus and P. gingivalis titers (per SD, aHR = 1.22; 95% CI, 1.04–1.43, p = 0.012), while AD mortality risk was increased with another composite (per SD, aHR = 1.46; 95% CI, 1.09–1.96, p = 0.017) loading highly on IgG for P. gingivalis , Prevotella intermedia , Prevotella nigrescens , Fusobacterium nucleatum , C. rectus , Streptococcus intermedius , Capnocylophaga Ochracea , and P. melaninogenica . This study provides evidence for an association between periodontal pathogens and AD, which was stronger for older adults. Effectiveness of periodontal pathogen treatment on reducing sequelae of neurodegeneration should be tested in randomized controlled trials. Show more

Keywords: Aging, Alzheimer’s disease, dementia, periodontal pathogens, periodontitis

DOI: 10.3233/JAD-200064

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Price: EUR 27.50

Cerebrospinal Fluid/Plasma Albumin Ratio as a Biomarker for Blood-Brain Barrier Impairment Across Neurodegenerative Dementias

Article Type: Research Article

Abstract: Background: Previous studies have shown an association between disruption of the blood-brain-barrier (BBB) and dementias of different etiologies. The protein concentration of cerebrospinal fluid (CSF) can be used as an indirect measurement for the permeability of the BBB using the CSF/plasma albumin quotient (Q-Alb) or total CSF protein. Objective: In the current study, we wanted to investigate Q-Alb and CSF protein concentration in dementias of different etiologies and the possible confounding factors. Methods: A total of 510 patients and healthy controls were included in the current study. The patients were diagnosed with Alzheimer’s disease (AD), dementia …with Lewy bodies (DLB), vascular dementia (VaD), or frontotemporal dementia (FTD). Results: We found that Q-Alb was significantly different between the groups (p = 0.002, F = 3.874). Patients with DLB and VaD showed the largest Q-Alb. Although not significant for CSF total protein, we found the same overall pattern for DLB and VaD. When examining confounding factors, we found a positive association with age and a lower Fazekas score in DLB as compared to VaD. Conclusion: These results suggest that Q-Alb can contribute to our understanding of the pathophysiological mechanisms in DLB, and Q-Alb may serve as a supplementary diagnostic marker. Furthermore, we found a positive association with age, which may be due to differences in vascular co-morbidities. In addition, in patients with DLB, the increased Q-Alb is not due to vascular lesions. Studies are needed to validate the possible diagnostic value of Q-Alb in a larger cohort. Show more

Keywords: albumin, Alzheimer’s disease, cerebrospinal fluid, CSF/plasma albumin quotient, frontotemporal dementia, Lewy body dementia, protein, Q-Alb, vascular dementia

DOI: 10.3233/JAD-200168

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Price: EUR 27.50

Proteomics Time-Course Study of App Knock-In Mice Reveals Novel Presymptomatic Aβ ₄₂-Induced Pathways to Alzheimer’s Disease Pathology

Article Type: Research Article

Abstract: Background: The 42 amino acids long amyloid-β peptide, Aβ42 , may initiate a cascade of events leading to the severe neurodegeneration observed in Alzheimer’s disease (AD) brain. However, the underlying molecular mechanisms remain to be established. Objective: To find early Aβ42 -induced AD related mechanisms, we performed a brain proteomics time-course study on a novel App knock-in AD mouse model, AppNL -F , expressing high levels of Aβ42 without AβPP overexpression artifacts. Methods: Hippocampus and cortex were analyzed separately by using 18 O-labelling mass spectrometry to reveal alterations in protein levels. Pathway …analysis of proteomics data was used to identify altered biological functions. Immunohistochemistry was used to further investigate a significant key regulatory protein. Results: Around 100 proteins were differently expressed in AppNL -F mice at each time point (3, 6, 9, and 18 months of age) as compared to wild type mice. Strikingly, already at 3 months of age—long before Aβ plaque development and memory impairment—several pathways, including long-term potentiation and synaptic plasticity, were downregulated, and neuritogenesis was increased. Huntingtin (HTT) was identified as an upstream regulator, i.e., a key protein affecting the levels of several proteins. Increased levels of HTT in hippocampus of AppNL -F mice was supported by immunofluorescence microscopy. Conclusion: Notably, the proteome was significantly altered already at 3 months of age, 6 months before the development of plaques. Differentially expressed proteins varied over time, indicating that increased Aβ42 levels initiate a cascade of events that eventually manifests in amyloid depositions, inflammation, and decline in memory. Show more

Keywords: Alzheimer’s disease, amyloid-β, App knock-in mouse model, ingenuity pathway analysis, proteomics

DOI: 10.3233/JAD-200028

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Price: EUR 27.50

Associations of Infectious Agents with Alzheimer’s Disease: A Systematic Review and Meta-Analysis

Article Type: Research Article

Abstract: Background: The role of infectious agents in the development of Alzheimer’s disease (AD) has long been debated, however, uncertainties still persist. Objective: We aimed to illuminate the associations between infectious agents and risk of AD comprehensively. Methods: Studies examining the associations between AD and infectious agents were identified through a systematic search of PubMed, Embase, and Cochrane library. A random-effects meta-analysis was conducted. Publication bias was explored using funnel plot. Results: Fifty-one studies were included in the systematic review, of which forty-seven studies with 108,723 participants and 4,039 AD cases were eligible for meta-analysis. …Evidence based on case control studies demonstrated that Chlamydia pneumoniae [odds ratio (OR): 4.39, 95% CI = 1.81–10.67; I2 = 68%)], Human herpes virus-6 (OR: 3.97, 95% CI = 2.04–7.75; I2 = 0%, p = 0.72), Epstein-Barr virus (OR:1.45, 95% CI = 1.00–2.08; I2 = 0%), Herpes simplex virus-1 (OR:1.34, 95% CI = 1.02–1.75; I2 = 0%), and the Herpesviridae family (OR:1.41, 95% CI = 1.15–1.74; I2 = 12%) infection were associated with a higher risk of AD. No significant evidence of publication bias was found. Conclusion: These findings strengthened the evidence that infection may play an important role in AD. Additional research is required to determine whether treatment strategies targeting infectious diseases to prevent AD are viable in the future. Show more

Keywords: Alzheimer’s disease, Chlamydia pneumoniae, Herpesviridae, infectious, meta-analysis

DOI: 10.3233/JAD-191337

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

Synaptic Vesicle Protein 2B Negatively Regulates the Amyloidogenic Processing of AβPP as a Novel Interaction Partner of BACE1

Article Type: Research Article

Abstract: Background: Given that amyloid-β (Aβ) peptide is produced and released at synapses, synaptic Aβ is one of the promising therapeutic targets to prevent synaptic dysfunction in Alzheimer’s disease (AD). Although Aβ production begins with the cleavage of the amyloid-β protein precursor (AβPP) by β-site AβPP cleaving enzyme 1 (BACE1), the mechanism on how BACE1 is involved in AβPP processing at synapses remains unclear. Objective: This study aimed to identify novel BACE1 interacting proteins regulating Aβ production at the synapse. Methods: BACE1 interacting proteins were pulled down using a mass spectrometry-based proteomics of wild-type (WT) rat brain …synaptoneurosome lysates utilizing anti-BACE1 antibody. Then, a novel BACE1 interactor was identified and characterized using experimental systems that utilized transfected cells and knockout (KO) mice. Results: Synaptic vesicle protein 2B (SV2B) was identified as a novel presynaptic interaction partner of BACE1. In HEK293 cells, co-overexpression of SV2B with BACE1 significantly reduced the sAβPPβ and Aβ levels released in the media; thus, SV2B overexpression negatively affected the AβPP cleavage by BACE1. Compared with those of WT mice, the hippocampal lysates of SV2B knockout mice had significantly elevated Aβ levels, whereas the β-secretase activity and the AβPP and BACE1 protein levels remained unchanged. Finally, a fractionation assay revealed that BACE1 was mislocalized in SV2B KO mice; hence, SV2B may be involved in BACE1 trafficking downregulating the amyloidogenic pathway of AβPP. Conclusion: SV2B has a novel role of negatively regulating the amyloidogenic processing of AβPP at the presynapses. Show more

Keywords: Alzheimer’s disease, amyloid-β , BACE1, SV2B, synapse

DOI: 10.3233/JAD-200071

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Price: EUR 27.50

What Could Be the Main Levers to Promote a Timely Diagnosis of Neurocognitive Disorders?

Authors: Garnier-Crussard, Antoine | Vernaudon, Julien | Auguste, Nicolas | Dauphinot, Virginie | Krolak-Salmon, Pierre

Article Type: Research Article

Abstract: Background: Neurocognitive disorders (NCD) are a growing health issue and the importance of diagnosis is still debated despite the benefits of making a diagnosis appearing to be greater than the risks. Objective: The aim of the present study was to explore the perception of the main benefits and risks to perform a diagnosis workup of NCD in a population of general practitioners (GPs), specialized physicians (SPs), other healthcare professionals (OHPs), and informal caregivers (ICs), and to identify the lowest perceived benefits and the highest perceived risks that could be levers to promote a diagnosis of NCD. …Methods: A standardized questionnaire was submitted to GPs, SPs, OHPs, and ICs aiming to evaluate the importance of eight benefits and eight risks related to NCD diagnosis (selected from the literature) for four prototypical clinical cases at different stages of the disease: subjective cognitive impairment/mild NCD, major NCD at mild/moderate stage, moderate stage with behavioral and psychotic symptoms, and severe stage. Results: The lowest perceived benefits of making an NCD diagnosis were “access to medical research”, “patient’s right to know”, and “initiation of symptomatic drug treatment”. The highest perceived risks of making an NCD diagnosis were “negative psychological impact for the patient”, “absence of disease-modifying treatment”, and “absence of suitable institution”. Conclusion: This study highlights the lowest perceived benefits and the highest perceived risks of making an NCD diagnosis. These benefits and risks could be modified to become levers to promote a personalized diagnosis of NCD. Show more

Keywords: Benefits and risks, ethical issues, neurocognitive disorders, personalized diagnosis, timely diagnosis

DOI: 10.3233/JAD-191253

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer’s Disease

Article Type: Research Article

Abstract: Many Alzheimer’s disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, …we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia. Show more

Keywords: Alzheimer’s disease, microglia polarization, neuropathic pain, shDNMT1

DOI: 10.3233/JAD-200099

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

Impact of 3-Day Combined Anodal Transcranial Direct Current Stimulation-Visuospatial Training on Object-Location Memory in Healthy Older Adults and Patients with Mild Cognitive Impairment

Authors: de Sousa, Angelica Vieira Cavalcanti | Grittner, Ulrike | Rujescu, Dan | Külzow, Nadine | Flöel, Agnes

Article Type: Research Article

Abstract: Background: Associative object-location memory (OLM) is known to decline even in normal aging, and this process is accelerated in patients with mild cognitive impairment (MCI). Given the lack of curative treatment for Alzheimer’s disease, activating cognitive resources during its preclinical phase might prevent progression to dementia.). Objective: To evaluate the effects of anodal transcranial direct current stimulation (atDCS) combined with an associative episodic memory training on OLM in MCI patients and in healthy elderly (HE). Methods: In a single-blind cross-over design, 16 MCI patients and 32 HE underwent a 3-day visuospatial OLM training paired with either …20 min or 30 s (sham) atDCS (1 mA, right temporoparietal cortex). Effects on immediate (training success) and long-term memory (1-month) were investigated by conducting Mixed Model analyses. In addition, the impact of combined intervention on within-session (online) and on between-session (offline) performance were explored. Results: OLM training+atDCS enhanced training success only in MCI patients, but not HE (difference n.s.). Relative performance gain was similar in MCI patients compared to HE under atDCS. No beneficial effect was found after 1 month. Exploratory analyses suggested a positive impact for online, but a negative effect on offline performance in MCI patients. In both groups, exploratory post-hoc analyses indicated an association between initially low-performers and greater benefit from atDCS. Conclusion: Cognitive training in MCI may be enhanced by atDCS, but further delineation of the impact of current brain state, as well as temporal characteristics of multi-session atDCS-training application, may be needed to induce longer-lasting effects. Show more

Keywords: Association learning, cognition, dementia, episodic memory, transcranial direct current stimulation

DOI: 10.3233/JAD-191234

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-22, 2020

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Baseline Results: The Association between Cardiovascular Risk and Preclinical Alzheimer’s Disease Pathology (ASCEND) Study

Article Type: Research Article

Abstract: Background: The rate of AD for African Americans (AAs) is 64% higher than for non-Hispanic White Americans (Whites). It is hypothesized that poor peripheral vascular function, in combination with genetics, stress, and inflammation may directly contribute to the accumulation of AD pathologic biomarkers. These risk factors may disproportionately affect AAs. Objective: Our objective was to determine if in a healthy middle-aged cohort at risk for AD (1) AD biomarkers in CSF differ by race, (2) peripheral vascular dysfunction and cognition are related to a higher burden of CSF AD biomarkers, and (3) these relationships differ by race. …Methods: We enrolled 82 cognitively normal, middle-aged (45 and older) adults including AAs and Whites at high risk for AD due to parental history. Study procedures included lumbar puncture, vascular ultrasound, and cognitive testing. Results: While participants were in overall good health, AAs exhibited poorer indices of preclinical vascular health, including higher central SBP, central MAP, and EndoPAT AI, a marker of arterial stiffness. AAs also had significantly less cerebrospinal fluid tau burden than Whites. After polynomial regression analysis, adjusted for age, gender, education, and ApoE4 status, race significantly modified the relationship between total tau, phospho-tau, and Trails B, a marker of executive function. Small differences in tau correlated with poorer cognition in AAs. Conclusion: In a healthy middle-aged cohort at risk for AD, AAs had worse peripheral vascular health and worse cognition than Whites. Despite lower tau burden overall, race modified the relationship between tau and cognition, such that small differences in tau between AAs was related to worse cognition when compared to Whites. Show more

Keywords: Alzheimer’s disease, cognition, hypertension, parental history, prevention, tau, vascular risk

DOI: 10.3233/JAD-191103

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Price: EUR 27.50

Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias in Older African American and White Veterans

Article Type: Research Article

Abstract: Background: Racial disparity in the epidemiology of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) has been reported. However, less is known about this disparity among Veterans. Objective: To estimate the racial disparity in AD/ADRD among the Veterans. Methods: Of the 5,413,418 Veterans≥65 years receiving care at the Veterans Health Administration (1999–2016), 4,045,269 were free of prevalent AD/ADRD, schizophrenia, or bipolar disorder at baseline. Of these, 432,469 were African American. Race was self-identified and incident AD/ADRD during 20 (median 6.7) years of follow-up was ascertained using International Classification of Diseases codes. Results: Patients had a …mean age of 70.4 (±6.6) years and 97.8% were men. Age-sex-adjusted incidence of AD/ADRD per 1,000 person-year was 19.3 and 10.8 for African American and white Veterans, respectively (age-sex-adjusted hazard ratio associated with African American race, 1.77; 95% confidence interval, 1.75–1.79; p < 0.0001). This association remained essentially unchanged after multivariable adjustment (hazard ratio, 1.67; 95% confidence interval, 1.65–1.69; p < 0.0001). Among the key baseline characteristics that were significant predictors of AD/ADRD in both races, stroke was a significantly stronger predictor among African Americans, and Hispanic ethnicity and depression among whites (p-value for all interaction,<0.0001). Conclusion: The findings of a higher incidence of AD/ADRD among African American Veterans is consistent with the findings in the general population reported in the literature, although the overall incidence appears to be lower than that in the general population. Future studies need to examine this disparity in incidence as well as the between-race heterogeneity in AD/ADRD risk. Show more

Keywords: dementia, health status disparities, incidence, race factors

DOI: 10.3233/JAD-191188

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

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TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort

Article Type: Research Article

Abstract: Pathologies associated with the Tar-DNA binding protein 43 KDa (TDP-43) are associated with neurodegenerative diseases and aging. Phosphorylation of cellular proteins is a well-accepted mechanism of biological control and can be associated with disease pathways. Phosphorylation state associated with TDP-43 associated pathology has not been investigated with respect to dementia status in a population representative sample. TDP-43 immunohistochemistry directed toward phosphorylated (TDP-43P) and unphosphorylated (TDP-43U) was assessed in sections of hippocampus and temporal cortex from 222 brains donated to the population representative Cambridge City over-75s Cohort. Relationships between dementia status and age at death for TDP-43 immunoreactive pathologies by phosphorylation …state were investigated. TDP-43 pathologies are common in the oldest old in the population and often do not conform to MacKenzie classification. Increasing age is associated with glial (TDP-43P) and neuronal inclusions (TDP-43P and TDP-43U), neurites, and granulovacuolar degeneration (GVD). Dementia status is associated with GVD and glial (TDP-43 P) and neural inclusions (TDP-43 P and U). Dementia severity was associated with glial (TDP-43P) and neuronal inclusions (TDP-43U and TDP-43P), GVD, and neurites. The associations between dementia severity and both glial cytoplasmic inclusions and GVD were independent from other pathologies and TDP-43 neuronal cytoplasmic inclusions. TDP-43 pathology contributes to dementia status and progression in a variety of ways in different phosphorylation states involving both neurons and glia, independently from age and from classic Alzheimer-related pathologies. TDP-43 pathologies as cytoplasmic inclusions in neurons or glia or as GVD contribute independently to dementia. Show more

Keywords: Aging, dementia, hippocampus, phosphorylation, population study, TAR-DNA binding protein of 43 kDa

DOI: 10.3233/JAD-191093

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

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Ca:Mg Ratio, APOE Cytosine Modifications, and Cognitive Function: Results from a Randomized Trial

Article Type: Research Article

Abstract: Background: Deterioration of ionized calcium (Ca2+ ) handling in neurons could lead to neurodegenerative disease. Magnesium (Mg) antagonizes Ca during many physiologic activities, including energy metabolism and catalyzation of demethylation from 5-methylcytosine(5-mC) to 5-hydroxymethylcytosine(5-hmC). Objective: To test the hypothesis that actively reducing the Ca:Mg intake ratio in the diet through Mg supplementation improves cognitive function, and to test whether this effect is partially mediated by modified cytosines in Apolipoprotein E (APOE). Methods: This study is nested within the Personalized Prevention of Colorectal Cancer Trial (PPCCT), a double-blind 2×2 factorial randomized controlled trial, which enrolled …250 participants from Vanderbilt University Medical Center. Target doses for both Mg and placebo arms were personalized. Results: Among those aged > 65 years old who consumed a high Ca:Mg ratio diet, we found that reducing the Ca:Mg ratio to around 2.3 by personalized Mg supplementation significantly improved cognitive function by 9.1% (p = 0.03). We also found that reducing the Ca:Mg ratio significantly reduced 5-mC at the cg13496662 and cg06750524 sites only among those aged > 65 years old (p values = 0.02 and 0.03, respectively). Furthermore, the beneficial effect of reducing the Ca:Mg ratio on cognitive function in those aged over 65 years was partially mediated by reductions in 5-mC levels (i.e., cg13496662 and cg06750524) in APOE (p for indirect effect = 0.05). Conclusion: Our findings suggest that, among those age 65 and over with a high dietary Ca:Mg ratio, optimal Mg status may improve cognitive function partially through modifications in APOE methylation. These findings, if confirmed, have significant implications for the prevention of cognitive aging and Alzheimer’s disease. Clinical Trial Registry number and website : #100106 https://clinicaltrials.gov/ct2/show/NCT03265483 Show more

Keywords: APOE methylation, calcium, cognitive function, magnesium, mediation analysis, ratio

DOI: 10.3233/JAD-191223

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

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Is Alzheimer’s Disease a Liver Disease of the Brain?

Authors: Bassendine, Margaret F. | Taylor-Robinson, Simon D. | Fertleman, Michael | Khan, Michael | Neely, Dermot

Article Type: Review Article

Abstract: Clinical specialization is not only a force for progress, but it has also led to the fragmentation of medical knowledge. The focus of research in the field of Alzheimer’s disease (AD) is neurobiology, while hepatologists focus on liver diseases and lipid specialists on atherosclerosis. This article on AD focuses on the role of the liver and lipid homeostasis in the development of AD. Amyloid-β (Aβ) deposits accumulate as plaques in the brain of an AD patient long before cognitive decline is evident. Aβ generation is a normal physiological process; the steady-state level of Aβ in the brain is determined by …balance between Aβ production and its clearance. We present evidence suggesting that the liver is the origin of brain Aβ deposits and that it is involved in peripheral clearance of circulating Aβ in the blood. Hence the liver could be targeted to decrease Aβ production or increase peripheral clearance. Show more

Keywords: Keywords: Alzheimer’s disease, apolipoprotein E, circadian, hepatitis C virus, liver, metabolic syndrome, small interfering RNAs

DOI: 10.3233/JAD-190848

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

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Aggregates of RNA Binding Proteins and ER Chaperones Linked to Exosomes in Granulovacuolar Degeneration of the Alzheimer’s Disease Brain

Article Type: Research Article

Abstract: Granulovacuolar degeneration (GVD) occurs in Alzheimer’s disease (AD) brain due to compromised autophagy. Endoplasmic reticulum (ER) function and RNA binding protein (RBP) homeostasis regulate autophagy. We observed that the ER chaperones GRP78/BiP, Sigma receptor 1 (SigR1), and VAPB were elevated in many AD patients’ subicular neurons. However, those neurons which were affected by GVD showed lower chaperone levels, and there was only minor co-localization of chaperones with GVD bodies (GVBs), suggesting that neurons lacking sufficient chaperone-mediated proteostasis enter the GVD pathway. Consistent with this notion, granular, incipient pTau aggregates in human AD and pR5 tau transgenic mouse neurons were regularly …co-localized with increased chaperone immunoreactivity, whereas neurons with mature neurofibrillary tangles lacked both the chaperone buildup and significant GVD. On the other hand, APP/PS1 (APPswe/PSEN1dE9) transgenic mouse hippocampal neurons that are devoid of pTau accumulation displayed only few GVBs-like vesicles, which were still accompanied by prominent chaperone buildup. Identifying a potential trigger for GVD, we found cytoplasmic accumulations of RBPs including Matrin 3 and FUS as well as stress granules in GVBs of AD patient and pR5 mouse neurons. Interestingly, we observed that GVBs containing aggregated pTau and pTDP-43 were consistently co-localized with the exosomal marker Flotillin 1 in both AD and pR5 mice. In contrast, intraneuronal 82E1-immunoreactive amyloid-β in human AD and APP/PS1 mice only rarely co-localized with Flotillin 1-positive exosomal vesicles. We conclude that altered chaperone-mediated ER protein homeostasis and impaired autophagy manifesting in GVD are linked to both pTau and RBP accumulation and that some GVBs might be targeted to exocytosis. Show more

Keywords: Endoplasmic reticulum chaperones, exosomes, FUS, granulovacuolar degeneration, Matrin 3, Sigma receptor 1 (SigR1), stress granules

DOI: 10.3233/JAD-190722

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

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Patients with Alzheimer’s Disease Have Increased Levels of Insulin-like Growth Factor-I in Serum but not in Cerebrospinal Fluid

Authors: Horvath, Alexandra | Salman, Zeinab | Quinlan, Patrick | Wallin, Anders | Svensson, Johan

Article Type: Research Article

Abstract: Background: Insulin-like growth factor-I (IGF-I) is important for amyloid-β (Aβ) metabolism, and also interacts with the brain vasculature. In previous IGF-I studies, it has not been evaluated whether Alzheimer’s disease (AD) patients had vascular comorbidities. Objective and Methods: A cross-sectional study of 40 consecutive non-diabetic AD patients and 36 healthy controls. We measured IGF-I in serum and cerebrospinal fluid (CSF) and also serum insulin. Mixed forms of AD and vascular dementia were excluded. Results: After adjustment for covariates including age, serum IGF-I level was higher in the AD group than in the controls, whereas CSF IGF-I …and serum insulin were unchanged. Binary logistic regression confirmed that high serum IGF-I was associated with increased prevalence of AD [adjusted Odds Ratio (OR) = 1.83, 95% confidence interval (CI): 1.005–3.32 per standard deviation (SD) increase in serum IGF-I]. This association was more robust after exclusion of patients receiving treatment with acetylcholinesterase inhibitors or N-methyl D-aspartate (NMDA) receptor antagonists (OR = 2.23, 95 % CI: 1.10–4.48). In the total study population (n = 76) as well in the AD group (n = 40), serum IGF-I correlated negatively with CSF Aβ1-42 , and CSF IGF-I correlated positively with CSF/serum albumin ratio, CSF total tau, and CSF phosphorylated tau. Conclusion: In AD patients without major brain vascular comorbidities, serum but not CSF levels of IGF-I were increased after correction for covariates. This association was strengthened by exclusion of patients receiving medical treatment. Overall, the results support the notion of IGF-I resistance in mild AD dementia. Show more

Keywords: Alzheimer’s disease, cerebral vascular pathology, cerebrospinal fluid, CSF AD biomarkers, IGF-I, serum

DOI: 10.3233/JAD-190921

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

Computer-Assisted Speech Analysis in Mild Cognitive Impairment and Alzheimer’s Disease: A Pilot Study from Shanghai, China

Article Type: Research Article

Abstract: Background: Language dysfunction is a frequently reported symptom in Alzheimer’s disease (AD). However, computer-assisted analysis of spontaneous speech in AD and mild cognitive impairment (MCI) is rarely used to date. Objective: To characterize the language impairment in AD and amnestic MCI (aMCI) with computer-based automatic analysis via the “Automatic Speech Recognition (ASR) software for cognitive impairment V1.3”. Methods: A total of 64 subjects, including 20 AD patients, 20 aMCI patients, and 24 healthy controls were recruited. All subjects underwent neuropsychological testing, and spontaneous speech samples were recorded through the description of the “Cookie-Theft Picture” and then …analyzed by the computerized software. Subsequently, we compared the speech parameters between the subjects and the controls. Results: We identified seven spontaneous speech parameters (percentage of silence duration, average duration of phrasal segments, average duration of silence segments, number of speech segments, number of long pauses, ratio of hesitation/speech counts and ratio of short pause/speech counts) demonstrating significant differences between the three groups (p < 0.05). All seven speech parameters significantly correlated with cognitive performance, with average duration of silence segments demonstrating the best correlation to cognitive performance on stepwise multiple linear regression analysis. Conclusion: Computer-assisted automated analysis of speech/silence segments demonstrated the potential to reflect the intrinsic linguistic impairment associated with MCI and AD. It has a promising prospect in the early detection of AD and assessment of disease severity. Show more

Keywords: Alzheimer’s disease, computer-assisted speech analysis, language impairment, mild cognitive impairment, spontaneous speech

DOI: 10.3233/JAD-191056

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

Amyloid-β Causes Mitochondrial Dysfunction via a Ca ²⁺-Driven Upregulation of Oxidative Phosphorylation and Superoxide Production in Cerebrovascular Endothelial Cells

Article Type: Research Article

Abstract: Cerebrovascular pathology is pervasive in Alzheimer’s disease (AD), yet it is unknown whether cerebrovascular dysfunction contributes to the progression or etiology of AD. In human subjects and in animal models of AD, cerebral hypoperfusion and hypometabolism are reported to manifest during the early stages of the disease and persist for its duration. Amyloid-β is known to cause cellular injury in both neurons and endothelial cells by inducing the production of reactive oxygen species and disrupting intracellular Ca2+ homeostasis. We present a mechanism for mitochondrial degeneration caused by the production of mitochondrial superoxide, which is driven by increased mitochondrial Ca2+ …uptake. We found that persistent superoxide production injures mitochondria and disrupts electron transport in cerebrovascular endothelial cells. These observations provide a mechanism for the mitochondrial deficits that contribute to cerebrovascular dysfunction in patients with AD. Show more

Keywords: Amyloid-β, calcium, mitochondria, superoxide, vascular endothelial cells

DOI: 10.3233/JAD-190964

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Price: EUR 27.50

Amyloid-β in Alzheimer’s Disease: A Study of Citation Practices of the Amyloid Cascade Hypothesis Between 1992 and 2019

Authors: Daly, Timothy | Houot, Marion | Barberousse, Anouk | Agid, Yves | Epelbaum, Stéphane

Article Type: Research Article

Abstract: The amyloid cascade hypothesis (ACH) has dominated contemporary biomedical research into Alzheimer’s disease (AD) since the 1990 s but still lacks definitive confirmation by successful clinical trials of anti-amyloid medicines in human AD. In this uncertain period regarding the centrality of amyloid-β (Aβ) in AD pathophysiology, and with the community apparently divided about the ACH’s validity, we used citation practices as a proxy for measuring how researchers have invested their belief in the hypothesis between 1992 and 2019. We sampled 445 articles citing Hardy & Higgins (1992, “HH92”) and classified the polarity of their HH92 citation according to Greenberg (2009)’s citation …taxonomy of positive, neutral, and negative citations, and then tested four hypotheses. We identified two major attitudes towards HH92: a majority (62%) of neutral attitudes with consistent properties across the time period, and a positive attitude (35%), tending to cite HH92 earlier on within the bibliography as time went by, tending to take HH92 as an established authority. Despite the majority of neutral HH92 citations, there was a positive majority of attitudes toward different versions of the ACH and anti-amyloid therapeutic strategies (65%), suggesting that the ACH has been dominant and has undergone significant refinement since 1992. Finally, of those 110 original articles within the sample also testing the ACH empirically, an overwhelming majority (89%) returned a pro-ACH test result, suggesting that the ACH’s central claim is reproducible. Further studies will quantify the extent to which results from different methods within such original studies convergence to provide a robust conclusion vis-à-vis Aβ’s pathogenicity in AD. Show more

Keywords: Alzheimer’s disease, amyloid cascade hypothesis, amyloid-β, belief, bibliometrics, citations, confirmation, Karl Popper, reproducibility, scientific bias

DOI: 10.3233/JAD-191321

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Price: EUR 27.50

Older Patients with Alzheimer’s Disease-Related Cortical Atrophy Who Develop Post-Operative Delirium May Be at Increased Risk of Long-Term Cognitive Decline After Surgery

Article Type: Research Article

Abstract: Background: Older surgical patients with Alzheimer’s disease (AD) dementia and delirium are at increased risk for accelerated long-term cognitive decline. Objective: Investigate associations between a probabilistic marker of preclinical AD, delirium, and long-term cognitive decline. Methods: The Successful Aging after Elective Surgery cohort includes older adults (≥70 years) without dementia who underwent elective surgery. 140 patients underwent preoperative magnetic resonance imaging and had≥6 months cognitive follow-up. Cortical thickness was measured in ‘AD-Signature’ regions. Delirium was evaluated each postoperative day by the Confusion Assessment Method. Cognitive performance was assessed using a detailed neuropsychological battery at baseline; months …1, 2, and 6; and every 6 months thereafter until 36 months. Using either a General Cognitive Performance composite (GCP) or individual test scores as outcomes, we performed linear mixed effects models to examine main effects of AD-signature atrophy and the interaction of AD-signature atrophy and delirium on slopes of cognitive change from post-operative months 2–36. Results: Reduced baseline AD-signature cortical thickness was associated with greater 36-month cognitive decline in GCP (standardized beta coefficient, β = –0.030, 95% confidence interval [–0.060, –0.001]). Patients who developed delirium who also had thinner AD signature cortex showed greater decline on a verbal learning test (β = –0.100 [–0.192, –0.007]). Conclusion: Patients with the greatest baseline AD-related cortical atrophy who develop delirium after elective surgery appear to experience the greatest long-term cognitive decline. Thus, atrophy suggestive of preclinical AD and the development of delirium may be high-risk indicators for long-term cognitive decline following surgery. Show more

Keywords: aging signature, Alzheimer’s disease signature, cognitive decline, cortical thickness, delirium, preclinical Alzheimer’s disease, post-operative, surgery

DOI: 10.3233/JAD-190380

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Price: EUR 27.50

Cognitive Correlates of Digital Clock Drawing Metrics in Older Adults with and without Mild Cognitive Impairment

Article Type: Research Article

Abstract: Background: A digital version of the clock drawing test (dCDT) provides new latency and graphomotor behavioral measurements. These variables have yet to be validated with external neuropsychological domains in non-demented adults. Objective: The current investigation reports on cognitive constructs associated with selected dCDT latency and graphomotor variables and compares performances between individuals with mild cognitive impairment (MCI) and non-MCI peers. Methods: 202 non-demented older adults (age 68.79 ± 6.18, 46% female, education years 16.02 ± 2.70) completed the dCDT and a comprehensive neuropsychological protocol. dCDT variables of interest included: total completion time (TCT), pre-first hand latency …(PFHL), post-clock face latency (PCFL), and clock face area (CFA). We also explored variables of percent time drawing (i.e., ‘ink time’) versus percent time not drawing (i.e., ‘think time’). Neuropsychological domains of interest included processing speed, working memory, language, and declarative memory. Results: Adjusting for age and premorbid cognitive reserve metrics, command TCT positively correlated with multiple cognitive domains; PFHL and PCFL negatively associated with worse performance on working memory and processing speed tests. For Copy, TCT, PCFL, and PFHL negatively correlated with processing speed, and CFA negatively correlated with language. Between-group analyses show MCI participants generated slower command TCT, produced smaller CFA, and required more command ‘think’ (% Think) than ‘ink’ (% Ink) time. Conclusion: Command dCDT variables of interest were primarily processing speed and working memory dependent. MCI participants showed dCDT differences relative to non-MCI peers, suggesting the dCDT may assist with classification. Results document cognitive construct validation to digital metrics of clock drawing. Show more

Keywords: Attention, cognition, cognitive aging, neuropsychology, processing speed

DOI: 10.3233/JAD-191089

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

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P301 L, an FTDP-17 Mutant, Exhibits Enhanced Glycation in vitro

Authors: Sonawane, Shweta Kishor | Chinnathambi, Subashchandrabose

Article Type: Research Article

Abstract: Background: Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer’s disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications. Objective: In this …study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau. Methods: Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy. Results: Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation. Conclusion: The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer’s disease. Show more

Keywords: Advanced glycation end products, Alzheimer’s disease, FTDP-17, tau glycation

DOI: 10.3233/JAD-191348

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

The Entorhinal Cortex Atrophy Score Is Diagnostic and Prognostic in Mild Cognitive Impairment

Article Type: Research Article

Abstract: Background: Structural magnetic resonance imaging (MRI) is routinely performed in patients with mild cognitive impairment (MCI), but diagnostic accuracy to detect early cerebral atrophy is limited. Objective: To validate the visual entorhinal cortex atrophy (ERICA) rating scale regarding diagnosis, biomarker status, neuropsychological profile, and dementia risk in MCI. Methods: The ERICA score was retrospectively assessed regarding its discrimination of MCI (n = 80) from subjective cognitive decline and Alzheimer’s disease (AD) dementia (n = 60, respectively), its prediction of conversion to dementia (median follow-up 28 months) and amyloid/tau biomarker status, and its association with neuropsychological tests. …Results: The ERICA score achieved 97% positive predictive value (PPV) for the presence of MCI. Discrimination between MCI and AD dementia (area under the curve: 0.71) was comparable to volumetry, and superior to the medial temporal lobe atrophy (MTA) score (p = 0.006). The PPV of the ERICA score for conversion to dementia was 83%, equivalent to tau status. It achieved 90% PPV for conversion when combined with tau, and 100% negative predictive value with verbal recall. While no measure predicted the predominantly positive amyloid status, the ERICA score was at least comparable to volumetry, and superior to the MTA score in predicting tau positivity (92% PPV for phospho-tau). The ERICA score was associated with verbal learning and memory, and, unlike the MTA score, also with AD-specific deficits in cued verbal recall. Conclusion: The ERICA score is a simple and valuable tool to exploit structural MRI for diagnosis and prognosis in MCI and is non-inferior to volumetry. Show more

Keywords: Alzheimer’s disease, entorhinal cortex, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-181150

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

Costs of Early Stage Alzheimer’s Disease in the United States: Cross-Sectional Analysis of a Prospective Cohort Study (GERAS-US)

Article Type: Research Article

Abstract: Background: Costs associated with early stages of Alzheimer’s disease (AD; mild cognitive impairment [MCI] and mild dementia [MILD]) are understudied. Objective: To compare costs associated with MCI and MILD due to AD in the United States. Methods: Data included baseline patient/study partner medical history, healthcare resource utilization, and outcome assessments as part of a prospective cohort study. Direct, indirect, and total societal costs were derived by applying standardized unit costs to resources for the 1-month pre-baseline period (USD2017). Costs/month for MCI and MILD cohorts were compared using analysis of variance models. To strengthen the confidence of …diagnosis, amyloid-β (Aβ ) tests were included and analyses were replicated stratifying within each cohort by amyloid status [+ /−]. Results: Patients (N = 1327) with MILD versus MCI had higher total societal costs/month ($4243 versus $2816; p < 0.001). These costs were not significantly different within each severity cohort by amyloid status. The largest fraction of overall costs were informal caregiver costs (45.1%) for the MILD cohort, whereas direct medical patient costs were the largest for the MCI cohort (39.0%). Correspondingly, caregiver time spent on basic activities of daily living (ADLs), instrumental ADLs, and supervision time was twice as high for MILD versus MCI (all p < 0.001). Conclusion: Early AD poses a financial burden, and despite higher functioning among those with MCI, caregivers were significantly impacted. The major cost driver was the patient’s clinical cognitive-functional status and not amyloid status. Differences were primarily due to rising need for caregiver support. Show more

Keywords: Amyloid, burden of illness, dementia, economic burden, florbetapir F18, mild cognitive impairment, societal burden, H8A-US-B004, NCT02951598

DOI: 10.3233/JAD-191212

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

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Increased Cerebrospinal Fluid Amyloid- β During Sleep Deprivation in Healthy Middle-Aged Adults Is Not Due to Stress or Circadian Disruption

Article Type: Research Article

Abstract: Background: Concentrations of soluble amyloid-β (Aβ ) oscillate with the sleep-wake cycle in the interstitial fluid of mice and cerebrospinal fluid (CSF) of humans. Further, the concentration of Aβ in CSF increases during sleep deprivation. Stress and disruption of the circadian clock are additional mechanisms hypothesized to increase CSF Aβ levels. Cortisol is a marker for both stress and has an endogenous circadian rhythm. Other factors such as glucose and lactate have been associated with changes in sleep-wake activity and/or Aβ . Objective: In this exploratory study, we used samples collected in a previous study …to examine how sleep deprivation affects Aβ , cortisol, lactate, and glucose in plasma and CSF from healthy middle-aged adults (N = 11). Methods: Eleven cognitively normal participants without evidence of sleep disturbance were randomized to sleep deprivation or normal sleep control. All participants were invited to repeat the study. Cortisol, lactate, glucose, and Aβ were measured in 2-h intervals over a 36-h period in both plasma and CSF. All concentrations were normalized to the mean prior to calculating mesor, amplitude, acrophase, and other parameters. Results: One night of sleep deprivation increases the overnight concentration of Aβ in CSF approximately 10%, but does not significantly affect cortisol, lactate, or glucose concentrations in plasma or CSF between the sleep-deprived and control conditions. Conclusion: These data suggest that sleep deprivation-related changes in CSF Aβ are not mediated by stress or circadian disruption as measured by cortisol. Show more

Keywords: Amyloid-β, cortisol, sleep deprivation

DOI: 10.3233/JAD-191122

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Price: EUR 27.50

Visual Search Efficiency in Mild Cognitive Impairment and Alzheimer’s Disease: An Eye Movement Study

Article Type: Research Article

Abstract: Background: Visual search abilities are essential to everyday life activities and are known to be affected in Alzheimer’s disease (AD). However, little is known about visual search efficiency in mild cognitive impairment (MCI), a transitive state between normal aging and dementia. Eye movement studies and machine learning methods have been recently used to detect oculomotor impairments in individuals with dementia. Objective: The aim of the present study is to investigate the association between eye movement metrics and visual search impairment in MCI and AD. Methods: 127 participants were tested: 43 healthy controls, 51 with MCI, and …33 with AD. They completed an eyetracking visual search task where they had to find a previously seen target stimulus among distractors. Results: Both patient groups made more fixations on the screen when searching for a target, with longer duration than controls. MCI and AD fixated the distractors more often and for a longer period of time than the target. Healthy controls were quicker and made less fixations when scanning the stimuli for the first time. Machine-learning methods were able to distinguish between controls and AD subjects and to identify MCI subjects with a similar oculomotor profile to AD with a good accuracy. Conclusion: Results showed that eye movement metrics are useful for identifying visual search impairments in MCI and AD, with possible implications in the early identification of individuals with high-risk of developing AD. Show more

Keywords: Alzheimer’s disease, eye movements, eyetracking, machine learning, mild cognitive impairment, visual attention, visual impairments, visual search

DOI: 10.3233/JAD-190690

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

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Interaction between Apolipoprotein E and Butyrylcholinesterase Genes on Risk of Alzheimer’s Disease in a Prospective Cohort Study

Article Type: Research Article

Abstract: Background: An epistatic interaction between the ɛ 4 allele of apolipoprotein E (APOE ɛ 4) gene and the K-variant of butyrylcholinesterase (BCHE-K ) genes has been previously reported to increase risk of Alzheimer’s disease (AD). However, these observations were largely from case-control studies with small sample sizes. Objective: To examine the interaction between APOE ɛ 4 and BCHE-K on: 1) the risk of incident AD and 2) rates of change in brain volumes and cognitive performance during the preclinical stages of AD in a prospective cohort study. Methods: The study sample for survival …analysis included 691 Caucasian participants (age at baseline, 58.4±9.9 years; follow-up time,16.9±9.7 years) from the Baltimore Longitudinal Study of Aging. The neuroimaging sample included 302 participants with 1,388 magnetic resonance imaging (MRI) scans. Cognitive performance was assessed in 703 participants over 4,908 visits. Results: A total of 122 diagnoses (79 AD, 43 mild cognitive impairment [MCI]) were identified. Participants with both APOE ɛ 4 and BCHE-K variants had a 3.7-fold greater risk of AD (Hazard ratio [HR] 95% CI=1.99–6.89, p < 0.001) compared to non-carriers of both genes (APOE ɛ 4 x BCHE-K interaction p = 0.025). There was no APOE ɛ 4-BCHE-K interaction effect on rate of cognitive decline and brain atrophy. Conclusion: The APOE and BCHE genes interact to influence risk of incident AD/MCI but not rates of brain atrophy and decline in cognitive performance before onset of cognitive impairment. This may suggest the epistatic interaction between APOE ɛ 4 and BCHE-K on AD risk is disease stage-dependent. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E4, Butyrylcholinesterase, epistaxis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-191335

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

Using Machine Learning to Predict Dementia from Neuropsychiatric Symptom and Neuroimaging Data

Article Type: Research Article

Abstract: Background: Machine learning (ML) is a promising technique for patient-specific prediction of mild cognitive impairment (MCI) and dementia development. Neuropsychiatric symptoms (NPS) might improve the accuracy of ML models but have barely been used for this purpose. Objectives: To investigate if baseline mild behavioral impairment (MBI) status used for NPS quantification along with brain morphology features are predictive of follow-up diagnosis, median 40 months later in patients with normal cognition (NC) or MCI. Method: Baseline neuroimaging, neuropsychiatric, and clinical data from 102 individuals with NC and 239 with MCI were extracted from the Alzheimer’s Disease Neuroimaging …Initiative database. Neuropsychiatric inventory questionnaire items were transformed to MBI domains using a published algorithm. Diagnosis at latest follow-up was used as the outcome variable and ground truth classification. A logistic model tree classifier combined with information gain feature selection was trained to predict follow-up diagnosis. Results: In the binary classification (NC versus MCI/AD), the optimal ML model required only two features from over 200, MBI total score and left hippocampal volume. These features correctly classified participants as remaining normal or developing cognitive impairment with 84.4% accuracy (area under the receiver operating characteristics curve [ROC-AUC] = 0.86). Seven features were selected for the three-class model (NC versus MCI versus dementia) achieving an accuracy of 58.8% (ROC-AUC=0.73). Conclusion: Baseline NPS, categorized for MBI domain and duration, have prognostic utility in addition to brain morphology measures for predicting diagnosis change using ML. MBI total score, followed by impulse dyscontrol and affective dysregulation were most predictive of future diagnosis. Show more

Keywords: Alzheimer’s disease, artificial intelligence, magnetic resonance imaging, mild behavioral impairment, mild cognitive impairment

DOI: 10.3233/JAD-191169

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

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Nicotine Promotes A βPP Nonamyloidogenic Processing via RACK1-Dependent Activation of PKC in SH-SY5Y-A βPP695 Cells

Article Type: Research Article

Abstract: Background: Accumulation of amyloid-β (Aβ ) peptides, generated from amyloid-β precursor protein (Aβ PP) amyloidogenic processing, is one of the most salient disease hallmarks of Alzheimer’s disease (AD). Nicotine is able to promote α -secretase-mediated Aβ PP nonamyloidogenic processing and increase the release of sAβ PPα and C-terminal fragment of 83 amino acids (C83). However, the potential molecular mechanism remains elusive. Objective: The aim of the present study was to investigate the effect of nicotine on Aβ PP processing in SH-SY5Y cells that stably express human Swedish mutant Aβ PP695 (SH-SY5Y-Aβ PP695). Methods: …The expression of Aβ PP and its C-terminal fragments including C99, C89, and C83, was measured in SH-SY5Y-Aβ PP695 cells treated with nicotine for 6 h. Protein kinase C (PKC) antagonist Ro30-8220 or agonist PMA was used to determine the role of PKC in Aβ PP processing. Lentivirus-mediated shRNA targeting receptor for activated C-kinase 1 (RACK1) gene was added into the media to knockdown RACK1 expression, and then Aβ PP processing was examined. Results: The results showed that 6 h of nicotine exposure increased the expression of α -secretase (ADAM10) and C83 in a dose dependent manner. While the β -secretase (BACE1), Aβ PP amyloidogenic processing products C89 and C99 as well as Aβ peptides (including Aβ 40 and Aβ 42 ) remained unchanged. We also found that nicotine elevated the expression of phosphorylated PKC (P-PKC) and RACK1 on the cytomembrane. PKC antagonist Ro30-8220 treatment prevented the increase of ADAM10 and C83 by nicotine. Genetic knockdown RACK1 significantly inhibited P-PKC, and consequently abolished the increase of ADAM10 and C83 by nicotine. Conclusion: Taken together, these results indicate that nicotine effectively promotes Aβ PP nonamyloidogenic processing via RACK1-dependent activation of PKC in SH-SY5Y-Aβ PP695 cells and could be a potential molecule for AD treatment. Show more

Keywords: Alzheimer’s disease, nicotine, protein kinase C, receptor for activated C-kinase 1

DOI: 10.3233/JAD-200003

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

A New Neurovascular Panel Discriminates Between Patients with Type 2 Diabetes Mellitus with Cognitive Impairment and Cognitive Impairment Alone

Article Type: Research Article

Abstract: Background: Recent studies showed that type 2 diabetes mellitus (T2DM) may increase the risk of cognitive impairment, but there are few biomarkers to diagnostically discriminate T2DM-associated cognitive impairment and cognitive impairment alone. In this study, we assessed certain cytokines involved in inflammation and vascular diseases and identified special panel of cytokines that could differentiate between T2DM and cognitive impairment. Objective: To investigate associations and differences between T2DM and cognitive impairment by cytokines analysis. Methods: A total of 264 participants were recruited, their blood samples were collected, and plasma and serum were separated and stored at – …80°C until the assessment of amyloid-β (Aβ )42 , Aβ 40 and 8 kinds of cytokines by Luminex multiplex assays. Results: Plasma Aβ 40 is higher whereas Aβ 42/40 ratio is lower in cognitive impairment and T2DM-associated cognitive impairment compared to other groups. As compared to health control, YKL-40 level was upregulated in cognitive impairment, PRGN was downregulated in T2DM associated cognitive impairment, OPN was substantially decreased in T2DM, and IL-6 was elevated in cognitive impairment and T2DM-associated cognitive impairment. Interestingly, VEGF and S100B were induced in T2DM when compared with cognitive impairment, and NSE level in T2DM-associated cognitive impairment is significantly lower than in T2DM or cognitive impairment. Conclusion: Aβ 42 , Aβ 40 , and Aβ 42/40 ratio cannot distinguish T2DM-associated cognitive impairment from cognitive impairment. Certain cytokines (YKL-40, NSE, and VEGF) have good performance in distinguishing T2DM-associated cognitive impairment from simple cognitive impairment. Taken together, this may improve the accuracy of the diagnosis and establishment of individualized therapy. Show more

Keywords: Biomarkers, cognitive impairment, serum cytokines, type 2 diabetes mellitus

DOI: 10.3233/JAD-200095

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

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Ethical Issues Raised by the Introduction of Artificial Companions to Older Adults with Cognitive Impairment: A Call for Interdisciplinary Collaborations

Authors: Portacolone, Elena | Halpern, Jodi | Luxenberg, Jay | Harrison, Krista L. | Covinsky, Kenneth E.

Article Type: Review Article

Abstract: Due to the high costs of providing long-term care to older adults with cognitive impairment, artificial companions are increasingly considered as a cost-efficient way to provide support. Artificial companions can comfort, entertain, and inform, and even induce a sense of being in a close relationship. Sensors and algorithms are increasingly leading to applications that exude a life-like feel. We focus on a case study of an artificial companion for people with cognitive impairment. This companion is an avatar on an electronic tablet that is displayed as a dog or a cat. Whereas artificial intelligence guides most artificial companions, this application …also relies on technicians “behind” the on-screen avatar, who via surveillance, interact with users. This case is notable because it particularly illustrates the tension between the endless opportunities offered by technology and the ethical issues stemming from limited regulations. Reviewing the case through the lens of biomedical ethics, concerns of deception, monitoring and tracking, as well as informed consent and social isolation are raised by the introduction of this technology to users with cognitive impairment. We provide a detailed description of the case, review the main ethical issues and present two theoretical frameworks, the “human-driven technology” platform and the emancipatory gerontology framework, to inform the design of future applications. Show more

Keywords: Dementia, ethics, robots, technology

DOI: 10.3233/JAD-190952

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Price: EUR 27.50

From Polygenic Scores to Precision Medicine in Alzheimer’s Disease: A Systematic Review

Authors: Harrison, Judith R. | Mistry, Sumit | Muskett, Natalie | Escott-Price, Valentina

Article Type: Research Article

Abstract: Background: Late-onset Alzheimer’s disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of an individual’s risk alleles, have been used to draw inferences about the pathological processes underpinning AD. Objective: This paper aims to systematically review how AD PRS are being used to study a range of outcomes and phenotypes related to neurodegeneration. Methods: We searched the literature from July 2008–July 2018 following PRISMA …guidelines. Results: 57 studies met criteria. The AD PRS can distinguish AD cases from controls. The ability of AD PRS to predict conversion from mild cognitive impairment (MCI) to AD was less clear. There was strong evidence of association between AD PRS and cognitive impairment. AD PRS were correlated with a number of biological phenotypes associated with AD pathology, such as neuroimaging changes and amyloid and tau measures. Pathway-specific polygenic scores were also associated with AD-related biologically relevant phenotypes. Conclusion: PRS can predict AD effectively and are associated with cognitive impairment. There is also evidence of association between AD PRS and other phenotypes relevant to neurodegeneration. The associations between pathway specific polygenic scores and phenotypic changes may allow us to define the biology of the disease in individuals and indicate who may benefit from specific treatments. Longitudinal cohort studies are required to test the ability of PGS to delineate pathway-specific disease activity. Show more

Keywords: alleles, Alzheimer’s disease, amyloid-beta peptides, cognitive dysfunction, genome-wide association study, multifactorial inheritance, neuroimaging, phenotype, precision medicine, single nucleotide polymorphism

DOI: 10.3233/JAD-191233

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

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Sex Differences in in vivo Alzheimer’s Disease Neuropathology in Late Middle-Aged Hispanics

Article Type: Research Article

Abstract: Background: Females may have a higher risk of dementia than males. It is not clear if sex differences in Alzheimer’s disease (AD) neuropathology explain the higher risk of dementia in females. Sex differences in AD neuropathology might begin in middle age, decades before the sex differences in dementia are apparent. Objective: To examine sex differences in in vivo AD neuropathology in late middle age. Methods: We conducted a cross-sectional comparison of AD biomarkers among 266 Hispanic males and females (mean age: 64.0; 71.8% females) without dementia. Amyloid burden was measured as global standardized uptake value ratio …(SUVR) with18 F-Florbetabenpositron emission tomography (PET). Neurodegeneration was ascertained as cortical thickness in AD signature areasusingbrain magnetic resonance imaging. Tau burden was measured as tau SUVR in the middle/inferior temporal gyri and medial temporal cortex with 18 F-MK-6240 in 75 of the 266 participants. Results: Females had higher amyloid SUVR and tau SUVR in the middle/inferior temporal gyri thanmales. However, femaleshad higher cortical thickness than males and performed better in a test of verbal memory despite having higher AD neuropathology burden. Conclusion: Higher amyloid and tauin femalescompared tomalesin late middle-agemay explainthe reported higher dementia risk in elderly females compared to males. Longitudinal follow-up is necessary to examine whether higher amyloid and tau burden in late middle age is followed by increased neurodegeneration and cognitive decline in females as compared with males. Show more

Keywords: Amyloid, cognition, Hispanics, neurodegeneration, sex differences, tau

DOI: 10.3233/JAD-191183

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

Diabetes Mellitus Increases Risk of Incident Dementia in APOE ɛ4 Carriers: A Meta-Analysis

Authors: Li, Lily | Cavuoto, Marina | Biddiscombe, Karen | Pike, Kerryn E.

Article Type: Research Article

Abstract: Background: Dementia is a devastating condition for older adults, with both modifiable (e.g., diabetes mellitus) and unmodifiable risk factors (e.g., APOE ɛ 4 allele). It remains unclear how, and to what extent, diabetes impacts dementia risk via both cerebrovascular and amyloid-β pathways. Objective: We conducted a quantitative meta-analysis to investigate the contribution of diabetes to incident dementia risk in people with ɛ 4 and, based on the vascular-related neuropathology of diabetes, whether the combination of these factors increases risk for vascular dementia versus Alzheimer’s disease (AD). Methods: Systematic literature searches were conducted using EMBASE, MEDLINE, …PsychINFO, and CINHAL databases. Pooled relative risk (RR) estimates were calculated using a random effects model, and subgroup analyses conducted across dementia subtypes. Results: Twelve studies were included, with a total of 16,200 participants. Considered concurrently, diabetes increased incident dementia risk an additional 35% for those with ɛ 4 (RR = 1.35, 95% CI = 1.13–1.63). Similar patterns were observed for AD and vascular dementia. Conclusion: Interventions to prevent co-morbid diabetes, and diabetes-related complications and neuropathological changes, may be one way of modifying dementia risk in the vulnerable ɛ 4 population. Show more

Keywords: Alzheimer’s disease, Apolipoproteins E, dementia, diabetes mellitus, risk factors, vascular dementia

DOI: 10.3233/JAD-191068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

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Generation of Transgenic Cynomolgus Monkeys Overexpressing the Gene for Amyloid-β Precursor Protein

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is the most common cause of dementia and understanding its pathogenesis should lead to improved therapeutic and diagnostic methods. Although several groups have developed transgenic mouse models overexpressing the human amyloid-β precursor protein (APP ) gene with AD mutations, with and without presenilin mutations, as well as APP gene knock-in mouse models, these animals display amyloid pathology but do not show neurofibrillary tangles or neuronal loss. This presumably is due to differences between the etiology of the aged-related human disease and the mouse models. Here we report the generation of two transgenic cynomolgus monkeys overexpressing the …human gene for APP with Swedish, Artic, and Iberian mutations, and demonstrated expression of gene tagged green fluorescent protein marker in the placenta, amnion, hair follicles, and peripheral blood. We believe that these nonhuman primate models will be very useful to study the pathogenesis of dementia and AD. However, generated Tg monkeys still have some limitations. We employed the CAG promoter, which will promote gene expression in a non-tissue specific manner. Moreover, we used transgenic models but not knock-in models. Thus, the inserted transgene destroys endogenous gene(s) and may affect the phenotype(s). Nevertheless, it will be of great interest to determine whether these Tg monkeys will develop tauopathy and neurodegeneration similar to human AD. Show more

Keywords: Amyloid-beta protein precursor, animal, cryopreservation, intracytoplasmic sperm injection (ICSI), primates, transgenic, vitrification, zygote

DOI: 10.3233/JAD-191081

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

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KALPANA: Advanced Spectroscopic Signal Processing Platform for Improved Accuracy to Aid in Early Diagnosis of Brain Disorders in Clinical Setting

Authors: Mandal, Pravat K. | Shukla, Deepika

Article Type: Editorial

Abstract: Magnetic resonance spectroscopy (MRS) plays a substantial role in the non-invasive detection of brain neurochemicals, antioxidants, and neurotransmitters. Quantitative monitoring of these neurochemicals and neurotransmitters in the brain has a profound application for the understanding of brain disorders. Significant progress in the MR scanner as well as MR pulse sequence development to detect in vivo neurochemicals has been accomplished. The processing of MR signal from these low abundant neurochemicals/neurotransmitters should be very robust and sensitive in order to provide distinctive observations of disease-related neurochemical alterations and their absolute quantitation to aid in early clinical diagnosis. We highlight the diversity …in currently available MRS processing tools, and recently introduced, KALPANA, a promising package integrating the end-to-end processing as well as robust quantitation of neurochemicals in a user-friendly approach through a graphical user interface. This further necessitates the futuristic need for advanced MRS processing pipeline and the respective readout can help in early diagnosis and prognosis of diseases in the clinical environment. Show more

Keywords: Absolute quantitation, clinical study, KALPANA, magnetic resonance spectroscopy, Matlab, platform, signal processing

DOI: 10.3233/JAD-191351

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

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“Choosing Wisely”: Apolipoprotein E Genetic Testing for the Diagnosis of Alzheimer’s Disease in Dementia Clinics

Article Type: Research Article

Abstract: Background: Apolipoprotein E (APOE ) ɛ 4 allele carriers have an increased risk of late-onset Alzheimer’s disease (AD). However, in the “Choosing Wisely” campaign for avoiding unnecessary medical tests, treatments, and procedures, APOE genetic testing is not recommended as a predictive test for AD. Objective: The aim of this study was to investigate the potential value of APOE genetic testing in a specific clinical context. Methods: Subjects with poor performance in the Korean version of the Mini-Mental Status Examination for dementia screening (MMSE-DS) with a Z-score of less than –1.5 were recruited from the …public health centers. All participants underwent APOE genetic testing. Family history of dementia (FHx) was confirmed if one or more first-degree relatives had dementia. Results: Among 349 subjects, 162 (46.4%) were diagnosed with AD. APOE ɛ 4 allele carriers had a much higher risk of AD in the group with FHx than in the group without FHx (OR = 15.81, 95% CI = 2.74–91.21 versus OR = 1.82, 95% CI = 1.00–3.27, z = 2.293, p = 0.011). The sensitivity, specificity, positive predictive value, and negative predictive value for the APOE ɛ 4 allele were 47.7%, 90.9%, 91.3%, and 46.5% in the group with FHx. Conclusion: It would be a wise choice to perform the APOE genetic testing for the diagnosis of AD in subjects with poor performance in a screening test and a family history of dementia. Show more

Keywords: Alzheimer’s disease, apolipoprotein genetic testing, odds ratio, sensitivity, specificity

DOI: 10.3233/JAD-190983

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Price: EUR 27.50

Cardiac Surgery is Associated with Biomarker Evidence of Neuronal Damage

Article Type: Research Article

Abstract: Background: Anesthesia and surgery is commonly associated with central nervous system sequelae and cognitive symptoms, which may be caused by neuronal injury. Neuronal injury can be monitored by plasma concentrations of the neuronal biomarkers tau and neurofilament light protein (NFL). Currently, there are no studies examining whether neuronal injury varies between surgical procedures. Objective: Our aim was to investigate if neuronal damage is more frequent after cardiac than after otolaryngeal surgery, as estimated by tau and NFL concentrations in plasma. Methods: Blood samples were drawn before, during, and after surgery and concentrations of tau, NFL, Aβ40 …, and Aβ42 were measured in 25 patients undergoing cardiac surgery (9 off-pump and 16 on-pump) and 26 patients undergoing otolaryngeal surgery. Results: Tau increased during surgery (1752%, p = 0.0001) and NFL rose seven days post-surgery (1090%, p < 0.0001) in patients undergoing cardiac surgery; even more in patients on-pump than off-pump. No changes were observed in patients undergoing otolaryngeal surgery and only minor fluctuations were observed for Aβ40 and Aβ42 . Conclusion: Cardiac surgery is associated with neuronal injury, which is aggravated by extracorporeal circulation. Analyses of NFL and tau in blood may guide development of surgical procedures to minimize neuronal damage, and may also be used in longitudinal clinical studies to assess the relationship of surgery with future neurocognitive impairment or dementia. Show more

Keywords: Cardiac surgery, cognitive impairment, dementia, extracorporeal circulation, neurofilament light protein, plasma, tau

DOI: 10.3233/JAD-191165

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

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Plasma Amyloid Concentration in Alzheimer’s Disease: Performance of a High-Throughput Amyloid Assay in Distinguishing Alzheimer’s Disease Cases from Controls

Article Type: Research Article

Abstract: Background: Collection of cerebrospinal fluid (CSF) for measurement of amyloid-β (Aβ) species is a gold standard in Alzheimer’s disease (AD) diagnosis, but has risks. Thus, establishing a low-risk blood Aβ test with high AD sensitivity and specificity is of outmost interest. Objective: We evaluated the ability of a commercially available plasma Aβ assay to distinguish AD patients from biomarker-healthy controls. Method: In a case-control design, we examined plasma samples from 44 AD patients (A + N+) and 49 controls (A–N–) from a memory clinic. AD was diagnosed using a combination of neuropsychological examination, CSF biomarker analysis and brain …imaging. Total Aβ40 and total Aβ42 in plasma were measured through enzyme-linked immunosorbent assay (ELISA) technology using ABtest40 and ABtest42 test kits (Araclon Biotech Ltd.). Receiver operating characteristic (ROC) analyses with outcome AD were performed, and sensitivity and specificity were calculated. Results: Plasma Aβ42/40 was weakly positively correlated with CSF Aβ42/40 (Spearman’s rho 0.22; p = 0.037). Plasma Aβ42/40 alone was not able to statistically significantly distinguish between AD patients and controls (AUC 0.58; 95% CI 0.46, 0.70). At a cut-point of 0.076 maximizing sensitivity and specificity, plasma Aβ42/40 had a sensitivity of 61.2% and a specificity of 63.6%. Conclusion: In this sample, the high-throughput blood Aβ assay was not able to distinguish well between AD patients and controls. Whether or not the assay may be useful in large-scale epidemiological settings remains to be seen. Show more

Keywords: Alzheimer’s disease, amyloid, diagnosis, high-throughput assay, plasma

DOI: 10.3233/JAD-200046

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

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Cerebrospinal Fluid Biomarkers in Cerebral Amyloid Angiopathy

Article Type: Research Article

Abstract: Background: There is limited data on cerebrospinal fluid (CSF) biomarkers in sporadic amyloid-β (Aβ) cerebral amyloid angiopathy (CAA). Objective: To determine the profile of biomarkers relevant to neurodegenerative disease in the CSF of patients with CAA. Methods: We performed a detailed comparison of CSF markers, comparing patients with CAA, Alzheimer’s disease (AD), and control (CS) participants, recruited from the Biomarkers and Outcomes in CAA (BOCAA) study, and a Specialist Cognitive Disorders Service. Results: We included 10 CAA, 20 AD, and 10 CS participants (mean age 68.6, 62.5, and 62.2 years, respectively). In unadjusted analyses, …CAA patients had a distinctive CSF biomarker profile, with significantly lower (p < 0.01) median concentrations of Aβ38 , Aβ40 , Aβ42 , sAβPPα , and sAβPPβ. CAA patients had higher levels of neurofilament light (NFL) than the CS group (p < 0.01), but there were no significant differences in CSF total tau, phospho-tau, soluble TREM2 (sTREM2), or neurogranin concentrations. AD patients had higher total tau, phospho-tau and neurogranin than CS and CAA groups. In age-adjusted analyses, differences for the CAA group remained for Aβ38 , Aβ40 , Aβ42 , and sAβPPβ. Comparing CAA patients with amyloid-PET positive (n = 5) and negative (n = 5) scans, PET positive individuals had lower (p < 0.05) concentrations of CSF Aβ42 , and higher total tau, phospho-tau, NFL, and neurogranin concentrations, consistent with an “AD-like” profile. Conclusion: CAA has a characteristic biomarker profile, suggestive of a global, rather than selective, accumulation of amyloid species; we also provide evidence of different phenotypes according to amyloid-PET positivity. Further replication and validation of these preliminary findings in larger cohorts is needed. Show more

Keywords: Alzheimer’s disease, amyloid-β , biomarkers, cerebral amyloid angiopathy, cerebrospinal fluid

DOI: 10.3233/JAD-191254

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

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Regional Amyloid Accumulation and White Matter Integrity in Cognitively Normal Individuals

Article Type: Research Article

Abstract: Background: Recent studies have shown that amyloid-β (Aβ) burden influenced white matter (WM) integrity before the onset of dementia. Objective: To assess whether the effects of Aβ burden on WM integrity in cognitively normal (CN) individuals were regionally specific. Methods: Our cohort consisted of 71 CNs from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who underwent both AV45 amyloid-PET and diffusion tensor imaging. Standardized uptake value ratio (SUVR) was computed across four bilateral regions of interest (ROIs) corresponding to four stages of in vivo amyloid staging model (Amyloid stages I–IV). Linear regression models were conducted …in entire CN group and between APOE ɛ 4 carriers and non-carriers. Results: Our results indicated that higher global Aβ-SUVR was associated with higher mean diffusivity (MD) in the entire CN group (p = 0.023), and with both higher MD (p = 0.015) and lower fractional anisotropy (FA) (p = 0.026) in APOE ɛ 4 carriers. Subregion analysis showed that higher Amyloid stage I-II Aβ-SUVRs were associated with higher MD (Stage-1: p = 0.030; Stage-2: p = 0.016) in the entire CN group, and with both higher MD (Stage-1: p = 0.004; Stage-2: p = 0.010) and lower FA (Stage-1: p = 0.022; Stage-2: p = 0.014) in APOE ɛ 4 carriers. No associations were found in APOE ɛ 4 non-carriers and in Amyloid stage III-IV ROIs. Conclusions: Our results indicated that the effects of Aβ burden on WM integrity in CNs might be regionally specific, particularly in Amyloid stage I-II ROIs, and modulated by APOE ɛ 4 status. Show more

Keywords: Amyloid PET, cognitively normal elders, diffusion tensor imaging, in vivo amyloid staging model, white matter integrity

DOI: 10.3233/JAD-191350

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

Synaptic Activity and (Neuro)Inflammation in Alzheimer’s Disease: Could Exosomes be an Additional Link?

Authors: Counil, Hermine | Krantic, Slavica

Article Type: Research Article

Abstract: Nanosized extracellular vesicles, known as exosomes, are produced by all cell types in mammalian organisms and have been recently involved in neurodegeneration. In the brain, both glia and neurons give rise to exosomes, which contribute to their intercellular communication. In addition, brain-derived exosomes have a remarkable property to cross the blood-brain-barrier bi-directionally. In this line, exosomes of central origin have been identified in peripheral circulation and already considered as putative blood biomarkers of neurodegenerative diseases, including Alzheimer’s disease (AD). Moreover, tentative use of exosomes as vehicle for the clearance of brain-born toxic proteins or, conversely, neuroprotective drug delivery, was also …envisaged. However, little is known about the precise role of exosomes in the control and regulation of neuronal functions. Based on the presence of subunits of glutamate receptors in neuron-derived exosomes on one hand, and complement proteins in astrocyte-derived exosomes on the other hand, we hypothesize that exosomes may participate in the control of neuronal excitability via inflammatory-like mechanisms both at the central level and from the periphery. In this review, we will focus on AD and discuss the mechanisms by which exosomes of neuronal, glial, and/or peripheral origin could impact on neuronal excitability either directly or indirectly. Show more

Keywords: Alzheimer’s disease, exosomes, glial cells, neuronal excitability, synaptic activity

DOI: 10.3233/JAD-191237

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

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Cognitive Functions as Predictors of Alzheimer’s Disease Biomarker Status in the European Prevention of Alzheimer’s Dementia Cohort

Authors: Terrera, Graciela Muniz | Harrison, John E. | Ritchie, Craig W. | Ritchie, Karen

Article Type: Research Article

Abstract: Alterations in Alzheimer’s disease (AD) biomarkers have been observed decades before the onset of dementia. Cognitive dysfunction, while central to the clinical diagnosis of AD, has long been considered as a late-stage phenomenon. This assumption is currently challenged and signals on some cognitive tests are now being observed within the preclinical stage. As part of the European Prevention of Alzheimer’s Dementia (EPAD) project, a battery of cognitive tests has been proposed (the EPAD Neuropsychological Examination, ENE) which is designed to detect cognitive changes in persons without clinical signs of AD but who are at high risk. Analysis of results from …the 361 participants with complete measures and without dementia recruited into the EPAD Longitudinal Cohort Study that the majority have elevated biomarker levels, with significant associations between an episodic verbal memory task and tau, while amyloid-β (Aβ) was associated with a central executive task. These preliminary findings suggest that profiles of cognitive performance may be specific to a given biomarker, with a primarily hippocampal task being associated with higher levels of tau and a frontal executive task being associated with higher levels of Aβ. While previous research has focused on the relationship between cognition and levels of Aβ, our findings suggest that p-tau may potentially be a more significant correlate. Show more

Keywords: Alzheimer’s disease, amyloid-β , biomarkers, cognition, diagnosis, neuropsychology, tau

DOI: 10.3233/JAD-191108

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

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Risk of Hospitalization in Patients with Alzheimer’s Disease and Lewy Body Dementia: Time to and Length of Stay

Authors: Oesterhus, Ragnhild | Dalen, Ingvild | Bergland, Anne K. | Aarsland, Dag | Kjosavik, Svein R.

Article Type: Research Article

Abstract: Background: Patients with dementia are at high risk of being hospitalized, but there is little knowledge whether this applies to all forms of dementia. Objective: To investigate if there are differences in hospitalization between patients with Alzheimer’s disease (AD) and Lewy body disease (LBD), and further, to compare admission rate with the general age-matched population. Methods: Patients (age 75.7±7.4) recently diagnosed with mild form of AD (n = 110) or LBD (n = 91) were included from outpatient clinics. The participants were followed from time of diagnosis, for five years or until death. Study outcomes were time to …first hospitalization after diagnosis, number of admissions, total number of hospital days, and length of stay. Age-standardized admission ratios were calculated. Time to first admission was analyzed using competing risks regression models, and differences in number of hospitalizations and hospital days were addressed using negative binomial regression models. Results: More than 77% of the patients were admitted, largely as unplanned hospitalizations. Patients with LBD had significantly shorter time until first hospitalization (median 1.28 years, 95% CI 0.93–1.67 versus AD: 2.32 years, 95% CI 1.74–3.31) and more unplanned hospital days (median 7 days, IQR 2–26), than patients with AD (2 days, IQR 0–11). Conclusion: Our data indicates that patients with LBD have shorter time until first admission and higher admission rate than AD patients. This imposes a great burden on patients, their family, and the health care system. More knowledge about hospital admissions of people with dementia is needed. Future studies should investigate strategies to avoid potentially preventable admissions. Show more

Keywords: Alzheimer’s disease, dementia, hospitalization, length of stay, Lewy body dementia, patient admission

DOI: 10.3233/JAD-191141

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

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Cdk5 Inhibitory Peptide Prevents Loss of Neurons and Alleviates Behavioral Changes in p25 Transgenic Mice

Article Type: Research Article

Abstract: Background: Accumulation of p25 is thought to be a causative risk factor for Alzheimer’s disease (AD). As a cleaved product of p35, p25 binds to cyclin-dependent kinase 5 (Cdk5) and leads to the hyperactivity of Cdk5. Then, Cdk5/p25 phosphorylates many pathological substrates related to neurodegenerative diseases. p25 transgenic (Tg) mouse model recaptures some pathological changes of AD, including tau hyperphosphorylation, neurofibrillary tangles, neuroinflammation, and neuronal death, which can be prevented by transgenic expression of Cdk5 inhibitory peptide (CIP) before the insult of p25. Objective: In the present study, we would like to know whether adeno-associated virus serotype-9 (AAV9)-mediated …CIP can protect neurons after insult of p25 in p25Tg mice. Methods: Administration of AAV9-CIP or control virus were delivered in the brain of p25Tg mice via intracerebroventricular infusions following the induction of p25. Western blotting, immunohistochemistry and immunofluorescence assessment, and animal behavioral evaluation were performed. Results: Brain atrophy, neuronal death, tau phosphorylation and inflammation in the hippocampus, and cognitive decline were observed in p25Tg mice. Administration of CIP but not the control virus in p25Tg mice reduced levels of tau phosphorylation and inflammation in the hippocampus, which is correlated with inhibition of brain atrophy and neuronal apoptosis in the hippocampus, and improvement of cognitive decline. Conclusion: Our results provide further evidence that the neurotoxicity of p25 can be alleviated by CIP. Show more

Keywords: Cdk5, Cdk5 inhibitory peptide, p25 transgenic mice, tau phosphorylation, neurodegeneration

DOI: 10.3233/JAD-191098

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

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Amyloid-β Fosters p35/CDK5 Signaling Contributing to Changes of Inhibitory Synapses in Early Stages of Cerebral Amyloidosis

Article Type: Research Article

Abstract: Early changes in inhibitory synapse connectivities are thought to contribute to the excitation/inhibition imbalance preceding neurodegeneration in Alzheimer’s disease (AD). Recently, we reported a robust increase in the level of different key-proteins of inhibitory synapses in hippocampal subregions of pre-symptomatic APPswe-PS1 mice, a model of cerebral amyloidosis. Besides increased inhibitory synaptic clusters on parvalbumin-positive projections in CA1 and CA3, we observed impaired communication between these two hippocampal areas of young APP-PS1 mice. Interestingly, the phosphorylation of gephyrin, a major organizer of inhibitory synapses, was also increased. Here, we demonstrate that the protein levels of CDK5, a kinase involved in the …phosphorylation of gephyrin, and its regulatory protein p35 are also significantly increased in hippocampal subregions of young APP-PS1 mice. Consistently, the expression of hAPP-swe in cultured hippocampal neurons resulted in higher p35-protein levels, indicating a possible molecular link between increased Aβ-production and the elevated p35/CDK5 levels seen in vivo . Further, a shRNA mediated downregulation of p35-expression in hippocampal neurons correlated with a decrease in gephyrin phosphorylation and in a reduced density of synaptic γ 2-GABAA -receptor clusters. These findings, together with the detection of gephyrin colocalization with CDK5 and p35 by immunostaining and proximity ligation experiments in vivo and in vitro , are supporting our hypothesis that Aβ has a profound impact on inhibitory network properties, likely mediated at least in part by p35/CDK5 signaling. This further underscores the impact of altered inhibitory synaptic transmission in AD. Show more

Keywords: Alzheimer’s disease, APP-PS1, CDK5, CDK5r1, γ2-GABAA receptor, inhibitory synapse, p35

DOI: 10.3233/JAD-190976

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2020

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Drug Repositioning for Alzheimer’s Disease: Finding Hidden Clues in Old Drugs

Authors: Ihara, Masafumi | Saito, Satoshi

Article Type: Review Article

Abstract: Although more than 100 years have passed since Alois Alzheimer reported a case of Alzheimer’s disease (AD), a definitive answer to the causes of cognitive impairment in the disease remains elusive. Despite significant enthusiasm and investment from the pharmaceutical industry, clinical trials of many disease-modifying drugs for AD have been largely unsuccessful. Drug repositioning (DR) or repurposing approaches are relatively inexpensive and more reliable compared to de novo drug development in AD. About 30% of clinical trials for AD in progress around the world use the DR method and hold potential in halting the current deadlock in treatment options. …By using drugs approved for other indications, these clinical trials target dysregulated pathways in AD with different or a combination of modes of action, including anti-amyloid, cardiovascular, anti-tau, anti-inflammatory, immunomodulatory, metabolic, neuroprotective, and neurotransmission-based approaches. For instance, anti-diabetic drugs, such as insulin, metformin, liraglutide, and dapagliflozin, and cardiovascular drugs, such as cilostazol, candesartan, telmisartan, prazosin, and dabigatran, could serendipitously provide previously unearthed benefits in AD. This is in line with recent thinking, which views AD as a complex multifactorial disorder, not dominated by one dominant biological factor, such as amyloid-β, and likely a confluence of many pathobiological mechanisms, including vascular dysregulation. Such increasingly available knowledge of phenotyping may be used to design ‘tailor-made’ DR and relatively homogeneous AD subpopulations specifically targeted with existing drugs based on known modes of action. It is thus expected that DR approaches will create a major paradigm shift in AD research and development. Show more

Keywords: Clinical trial, drug repositioning, drug reprofiling, drug repurposing, drug rescue

DOI: 10.3233/JAD-200049

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Price: EUR 27.50

Accuracy of MRI Classification Algorithms in a Tertiary Memory Center Clinical Routine Cohort

Article Type: Research Article

Abstract: Background: Automated volumetry software (AVS) has recently become widely available to neuroradiologists. MRI volumetry with AVS may support the diagnosis of dementias by identifying regional atrophy. Moreover, automatic classifiers using machine learning techniques have recently emerged as promising approaches to assist diagnosis. However, the performance of both AVS and automatic classifiers has been evaluated mostly in the artificial setting of research datasets. Objective: Our aim was to evaluate the performance of two AVS and an automatic classifier in the clinical routine condition of a memory clinic. Methods: We studied 239 patients with cognitive troubles from a …single memory center cohort. Using clinical routine T1-weighted MRI, we evaluated the classification performance of: 1) univariate volumetry using two AVS (volBrain and Neuroreader™); 2) Support Vector Machine (SVM) automatic classifier, using either the AVS volumes (SVM-AVS), or whole gray matter (SVM-WGM); 3) reading by two neuroradiologists. The performance measure was the balanced diagnostic accuracy. The reference standard was consensus diagnosis by three neurologists using clinical, biological (cerebrospinal fluid) and imaging data and following international criteria. Results: Univariate AVS volumetry provided only moderate accuracies (46% to 71% with hippocampal volume). The accuracy improved when using SVM-AVS classifier (52% to 85%), becoming close to that of SVM-WGM (52 to 90%). Visual classification by neuroradiologists ranged between SVM-AVS and SVM-WGM. Conclusion: In the routine practice of a memory clinic, the use of volumetric measures provided by AVS yields only moderate accuracy. Automatic classifiers can improve accuracy and could be a useful tool to assist diagnosis. Show more

Keywords: All cognitive disorders/dementia, Alzheimer’s disease, assessment of cognitive disorders/dementia, magnetic resonance imaging, volumetric MRI

DOI: 10.3233/JAD-190594

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Price: EUR 27.50

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