Journal of Alzheimer's Disease - Volume 66, issue 1

Authors: Evered, L. | Silbert, B. | Knopman, D.S. | Scott, D.A. | DeKosky, S.T. | Rasmussen, L.S. | Oh, E.S. | Crosby, G. | Berger, M. | Eckenhoff, R.G. | The Nomenclature Consensus Working Group

Article Type: Research Article

Abstract: Cognitive change affecting patients after anaesthesia and surgery has been recognised for more than 100 yr. Research into cognitive change after anaesthesia and surgery accelerated in the 1980s when multiple studies utilised detailed neuropsychological testing for assessment of cognitive change after cardiac surgery. This body of work consistently documented decline in cognitive function in elderly patients after anaesthesia and surgery, and cognitive changes have been identified up to 7.5 yr afterwards. Importantly, other studies have identified that the incidence of cognitive change is similar after non-cardiac surgery. Other than the inclusion of non-surgical control groups to calculate postoperative cognitive dysfunction, research into …these cognitive changes in the perioperative period has been undertaken in isolation from cognitive studies in the general population. The aim of this work is to develop similar terminology to that used in cognitive classifications of the general population for use in investigations of cognitive changes after anaesthesia and surgery. A multispecialty working group followed a modified Delphi procedure with no prespecified number of rounds comprised of three face-to-face meetings followed by online editing of draft versions. Two major classification guidelines [Diagnostic and Statistical Manual for Mental Disorders, fifth edition (DSM-5) and National Institute for Aging and the Alzheimer Association (NIA-AA)] are used outside of anaesthesia and surgery, and may be useful for inclusion of biomarkers in research. For clinical purposes, it is recommended to use the DSM-5 nomenclature. The working group recommends that ‘perioperative neurocognitive disorders’ be used as an overarching term for cognitive impairment identified in the preoperative or postoperative period. This includes cognitive decline diagnosed before operation (described as neurocognitive disorder ); any form of acute event (postoperative delirium ) and cognitive decline diagnosed up to 30 days after the procedure (delayed neurocognitive recovery ) and up to 12 months (postoperative neurocognitive disorder ). Show more

Keywords: Cognition disorders, delirium, neurocognitive disorders, postoperative complications

DOI: 10.3233/JAD-189004

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 1-10, 2018

Authors: Grizzanti, John | Corrigan, Rachel | Casadesus, Gemma

Article Type: Review Article

Abstract: Type II diabetes (T2D) has been identified as a major risk factor for the development of Alzheimer’s disease (AD). Interestingly, both AD and T2D have similar characteristics including amyloid peptide aggregation, decreased metabolism, and increased oxidative stress and inflammation. Despite their prevalence, therapies for these diseases are limited. To date, most therapies for AD have targeted amyloid-β or tau. Unfortunately, most of these clinical trials have been largely unsuccessful, creating a crucial need for novel therapies. A number of studies have shown that metabolic hormone therapies are effective at ameliorating high blood glucose levels in diabetics as well as improving …cognitive function in AD and mild cognitive impairment patients. Pramlintide, a synthetic analogue of the pancreatic hormone amylin, has been developed and used for years now as a treatment for both type I diabetes and T2D due to the loss of β-islet cells responsible for producing amylin. Importantly, recent data demonstrates its potential therapeutic role for AD as well. This review aims at addressing parallels between T2D and AD at a pathological and functional level, focusing on amylin signaling as a key, overlapping mediator in both diseases. The potential therapeutic use of this hormone to treat AD will also be explored from a mechanistic viewpoint. Show more

Keywords: Alzheimer’s disease, amylin, cognition, pramlintide, type II diabetes

DOI: 10.3233/JAD-180433

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 11-23, 2018

Authors: Doig, Andrew J.

Article Type: Review Article

Abstract: The dominant model for Alzheimer’s disease (AD) is the amyloid cascade hypothesis, in which the accumulation of excess amyloid-β (Aβ) leads to inflammation, excess glutamate and intracellular calcium, oxidative stress, tau hyperphosphorylation and tangle formation, neuronal loss, and ultimately dementia. In a cascade, AD proceeds in a unidirectional fashion, with events only affecting downstream processes. Compelling evidence now exists for the presence of positive feedback loops in AD, however, involving oxidative stress, inflammation, glutamate, calcium, and tau. The pathological state of AD is thus a system of positive feedback loops, leading to amplification of the initial perturbation, rather than a …linear cascade. Drugs may therefore be effective by targeting numerous points within the loops, rather than concentrating on upstream processes. Anti-inflammatories and anti-oxidants may be especially valuable, since these processes are involved in many loops and hence would affect numerous processes in AD. Show more

Keywords: Aggregation, amyloid, amyloid-β protein precursor, directed acyclic graph, drug discovery, peptide, systems biology

DOI: 10.3233/JAD-180583

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 25-36, 2018

Authors: Zuckerman, Scott L. | Brett, Benjamin L. | Jeckell, Aaron | Yengo-Kahn, Aaron M. | Solomon, Gary S.

Article Type: Review Article

Abstract: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by the presence of abnormally phosphorylated tau protein in the depths of one or more cortical sulci. Controversy over the risk of CTE and neurologic disorders later in life among contact sport athletes has taken hold in the public spotlight, most notably in American football. Players, parents, coaches, and legislators have taken action based on the commonly held notion that contact sports invariably lead to neurodegenerative disorders. However, to fully understand the science behind this assumed association, a critical appraisal of the evidence is warranted. With regards to CTE in sports, …the objectives of the current report are to: 1) describe the history of CTE, 2) review current CTE definitions, 3) critically evaluate the empiric data, divided into all contact sports and exclusively American football, and 4) summarize notable themes for future research. Show more

Keywords: Chronic traumatic encephalopathy, concussion, football, neurodegenerative diseases, sports, traumatic brain injury

DOI: 10.3233/JAD-180218

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 37-55, 2018

Authors: Trumbore, Conrad N.

Article Type: Research Article

Abstract: Amyloid-β oligomers (AβO) have been proposed as neurotoxins in the synaptic dysfunction that precedes Alzheimer’s disease symptoms. Human and animal model studies report that senile plaques contain a halo of AβO molecules surrounding these plaques. A far smaller number of oligomers are distributed widely in plaque-free regions. It has been suggested that oligomers migrate from halos to nearby synapses and are incorporated into both pre- and postsynaptic terminals. These two types of oligomers have two different toxicities when extracted and injected in animal models. This paper proposes a shear-energy based explanation for the data in these studies. Shear hypotheses in …the preceding three papers in this series are applied to suggest how the hydrodynamics and resulting shear patterns explain the spatial distribution of both AβO types, the apparent synapse loss in the vicinity of plaque particles, and possible reasons for the differing toxicities. A shear-based mechanism is proposed for the preferential migration of locally shear-excited Aβ molecules into the synaptic cleft. It is proposed that high energy laminar shear generated by the forced diversion of interstitial fluid around the flow-impeding plaque particle is responsible for the formation of AβOs around the plaque. It is suggested that in plaque-free regions, a different type of AβO with different toxicity is generated by lower energy shear flow around synapses, depositing AβO within the synapse from either the neuron membrane surface or by prion-like seeding within the synaptic cleft by locally-sheared Aβ molecules near the synapse entry. Show more

Keywords: Amyloid, amyloid-β, oligomers, prion, seeding, shear energy, synapse, synaptic cleft

DOI: 10.3233/JAD-171080

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 57-73, 2018

Authors: Emmerzaal, Tim L. | Rodenburg, Richard J. | Tanila, Heikki | Verweij, Vivienne | Kiliaan, Amanda J. | Kozicz, Tamas

Article Type: Short Communication

Abstract: Alzheimer’s disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse …model. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, electron transport complex II, electron transport complex IV, mice, mitochondria

DOI: 10.3233/JAD-180337

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 75-82, 2018

Authors: Mallo, Sabela C. | Ismail, Zahinoor | Pereiro, Arturo X. | Facal, David | Lojo-Seoane, Cristina | Campos-Magdaleno, María | Juncos-Rabadán, Onésimo

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are non-cognitive, behavioral, or psychiatric symptoms, common in mild cognitive impairment (MCI) and associated with a higher risk of dementia. Mild behavioral impairment (MBI) is a validated diagnostic entity, that describes the emergence of later life NPS in pre-dementia states. The Mild Behavioral Impairment Checklist (MBI-C) is the first measure developed to assess MBI. Objective: To estimate the prevalence of MBI in people with MCI and to study the score distribution, sensitivity, specificity, diagnostic utility of the MBI-C, and its correlations with neuropsychological tests. Methods: One hundred eleven MCI participants were evaluated …with the Questionnaire for Subjective Memory Complaints (QSMC), Mini-Mental State Examination, Cambridge Cognitive Assessment-Revised, Neuropsychiatric Inventory-Questionnaire (NPI-Q), Geriatric Depression Scale-15 items (GDS-15), Lawton and Brody Index, and the MBI-C, which was administered by phone to participants’ informants. Descriptive, logistic regression, ROC curve, and bivariate correlations analyses were performed. Results: MBI diagnosis prevalence was 14.2%. The total MBI-C score differentiated people with MBI at a cutoff-point of 6.5, optimizing sensitivity and specificity. MBI-C total score correlated positively with NPI-Q, QSMC, GDS-15, and Lawton and Brody Index. Conclusion: The total MBI-C score, obtained by phone administration, is sensitive for detecting MBI in people with MCI. The MBI-C scores indicated that MCI participants had subtle NPS that were correlated to their subjective memory complaints reported by informants, depressive symptoms, and negatively with Instrumental Activities of Daily Living. Further research should be done to clarify the predictive role of NPS in MCI for incident dementia. Show more

Keywords: Behavioral and psychological symptoms of dementia, dementia, mild behavioral impairment, mild cognitive impairment, neuropsychiatric symptoms, preclinical dementia, prodromal dementia

DOI: 10.3233/JAD-180131

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 83-95, 2018

Authors: O’Bryant, Sid E. | Zhang, Fan | Johnson, Leigh A. | Hall, James | Edwards, Melissa | Grammas, Paula | Oh, Esther | Lyketsos, Constantine G. | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: To date, the therapeutic paradigm for Alzheimer’s disease (AD) has focused on a single intervention for all patients. However, a large literature in oncology supports the therapeutic benefits of a precision medicine approach to therapy. Here we test a precision-medicine approach to AD therapy. Objective: To determine if a baseline, blood-based proteomic companion diagnostic predicts response to NSAID therapy. Methods: Proteomic assays of plasma from a multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to rofecoxib (25 mg once daily), naproxen (220 mg twice-daily) or placebo. Results: 474 participants with mild-to-moderate …AD were screened with 351 enrolled into the trial. Using support vector machine (SVM) analyses, 89% of the subjects randomized to either NSAID treatment arms were correctly classified using a general NSAID companion diagnostic. Drug-specific companion diagnostics yielded 98% theragnostic accuracy in the rofecoxib arm and 97% accuracy in the naproxen arm. Conclusion: Inflammatory-based companion diagnostics have significant potential to identify select patients with AD who have a high likelihood of responding to NSAID therapy. This work provides empirical support for a precision medicine model approach to treating AD. Show more

Keywords: Alzheimer’s disease, bioinformatics, biomarkers, clinical trial, inflammation, precision medicine, proteomics

DOI: 10.3233/JAD-180619

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 97-104, 2018

Authors: Laugisch, Oliver | Johnen, Andreas | Maldonado, Alejandra | Ehmke, Benjamin | Bürgin, Walter | Olsen, Ingar | Potempa, Jan | Sculean, Anton | Duning, Thomas | Eick, Sigrun

Article Type: Research Article

Abstract: Background: Recent studies suggest a link between periodontitis and Alzheimer’s disease (AD). Objective: Verification of the presence of periodontal pathogens and the intrathecal generation of pathogen-specific antibodies in 20 patients with AD and 20 with other forms of dementia (DEM-noAD). Methods: Clinical periodontal indices were recorded. Cerebrospinal fluid (CSF) was analyzed for total tau protein (T-tau) and amyloid-β (Aβ1-42 ). In serum and CSF, antibody levels against Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans , and Treponema species were quantified. The presence of selected bacteria and inflammatory biomarkers were determined in periodontium, serum, and CSF. …Results: In line with diagnoses, CSF-levels of Aβ1-42 were significantly lower in AD than DEM-noAD patients. Periodontal destruction and inflammation were omnipresent with no difference between groups. P. gingivalis , T. forsythia, and Treponema species were detected in more than 50% of subgingival biofilm samples, but neither in serum nor in the CSF. Elevated levels of anti-pathogen antibodies in CSF of 16 patients (7 AD; 9 DEM-noAD) compared to serum highlight a possibility of the intrathecal immune response to pathogens. There was no significant difference in antibodies levels against selected bacteria in CSF and serum between groups. Multivariate regression analysis and general linear models revealed an association of the T-tau level in AD group with both serum levels of anti-P. gingivalis antibodies and MCP-1/CCL-2. Conclusion: Periodontal pathogens may enter the brain and stimulate a local immune response. However, in patients with dementia at the age up to 70 years, periodontal pathogens do not act as a trigger for developing AD. Show more

Keywords: Alzheimer’s disease, dementia, periodontitis, periodontal pathogens, Porphyromonas gingivalis

DOI: 10.3233/JAD-180620

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 105-114, 2018

Authors: Ehrenberg, Alexander J. | Suemoto, Claudia K. | França Resende, Elisa de Paula | Petersen, Cathrine | Leite, Renata Elaine Paraizo | Rodriguez, Roberta Diehl | Ferretti-Rebustini, Renata Eloah de Lucena | You, Michelle | Oh, Jun | Nitrini, Ricardo | Pasqualucci, Carlos Augusto | Jacob-Filho, Wilson | Kramer, Joel H. | Gatchel, Jennifer R. | Grinberg, Lea T.

Article Type: Research Article

Abstract: Clarifying the relationships between neuropsychiatric symptoms and Alzheimer’s disease (AD)-related pathology may open avenues for effective treatments. Here, we investigate the odds of developing neuropsychiatric symptoms across increasing burdens of neurofibrillary tangle and amyloid-β pathology. Participants who passed away between 2004 and 2014 underwent comprehensive neuropathologic evaluation at the Biobank for Aging Studies from the Faculty of Medicine at the University of São Paulo. Postmortem interviews with reliable informants were used to collect information regarding neuropsychiatric and cognitive status. Of 1,092 cases collected, those with any non-Alzheimer pathology were excluded, bringing the cohort to 455 cases. Braak staging was used …to evaluate neurofibrillary tangle burden, and the CERAD neuropathology score was used to evaluate amyloid-β burden. The 12-item neuropsychiatric inventory was used to evaluate neuropsychiatric symptoms and CDR-SOB score was used to evaluate dementia status. In Braak I/II, significantly increased odds were detected for agitation, anxiety, appetite changes, depression, and sleep disturbances, compared to controls. Increased odds of agitation continue into Braak III/IV. Braak V/VI is associated with higher odds for delusions. No increased odds for neuropsychiatric symptoms were found to correlate with amyloid-β pathology. Increased odds of neuropsychiatric symptoms are associated with early neurofibrillary tangle pathology, suggesting that subcortical neurofibrillary tangle accumulation with minimal cortical pathology is sufficient to impact quality of life and that neuropsychiatric symptoms are a manifestation of AD biological processes. Show more

Keywords: Alzheimer’s disease, amyloid plaques, anxiety, appetite behavior, depression, neurofibrillary tangles, neuropathology, neuropsychiatry, sleep, tau protein

DOI: 10.3233/JAD-180688

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 115-126, 2018

Authors: Yeo, Si Ning | Lee, Tih Shih | Sng, Wei Theng | Heo, Min Quan | Bautista, Dianne | Cheung, Yin Bun | Zhang, Hai Hong | Wang, Chuanchu | Chin, Zheng Yang | Feng, Lei | Zhou, Juan | Chong, Mei Sian | Ng, Tze Pin | Krishnan, K. Ranga | Guan, Cuntai

Article Type: Research Article

Abstract: Background: Cognitive training has been demonstrated to improve cognitive performance in older adults. To date, no study has explored personalized training that targets the brain activity of each individual. Objective: This is the first large-scale trial that examines the usefulness of personalized neurofeedback cognitive training. Methods: We conducted a randomized-controlled trial with participants who were 60–80 years old, with Clinical Dementia Rating (CDR) score of 0–0.5, Mini-Mental State Examination (MMSE) score of 24 and above, and with no neuropsychiatric diagnosis. Participants were randomly assigned to the Intervention or Waitlist-Control group. The training system, BRAINMEM, has attention, …working memory, and delayed recall game components. The intervention schedule comprised 24 sessions over eight weeks and three monthly booster sessions. The primary outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) total score after the 24-session training. Results: There were no significant between-subjects differences in overall cognitive performance post-intervention. However, a sex moderation effect (p = 0.014) was present. Men in the intervention group performed better than those in the waitlist group (mean difference, +4.03 (95% CI 0.1 to 8.0), p = 0.046. Among females, however, both waitlist-control and intervention participants improved from baseline, although the between-group difference in improvement did not reach significance. BRAINMEM also received positive appraisal and intervention adherence from the participants. Conclusion: A personalized neurofeedback intervention is potentially feasible for use in cognitive training for older males. The sex moderation effect warrants further investigation and highlights the importance of taking sex into account during cognitive training. Show more

Keywords: Brain-computer interface, cognitive training, older adults, personalized neurofeedback

DOI: 10.3233/JAD-180450

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 127-138, 2018

Authors: Nagata, Tomoyuki | Shinagawa, Shunichiro | Nakajima, Shinichiro | Mimura, Masaru | Shigeta, Masahiro

Article Type: Research Article

Abstract: Background/Objective: To assess associations between improvements in neuropsychiatric symptoms (NPS) and neurocognitive change in patients with Alzheimer’s disease (AD) during treatment using the Clinical Antipsychotic Trials of Intervention Effectiveness–Alzheimer Disease (CATIE-AD) dataset. Methods: AD outpatients with NPS who needed pharmacological treatment (n  = 421) were followed up with antipsychotics, citalopram, or placebo for up to 36 weeks (mean±SD = 252±52 days). The study aim was to investigate associations between improvement in each NPS evaluating scale (by Clinical Global Impression of Change [CGI-C], Neuropsychiatric Inventory [NPI], or Brief Psychiatric Scale [BPRS]) at endpoint (week 36 or early termination [ET], n … = 340) and neurocognitive change (change score in the Mini-Mental State Examination [MMSE] between endpoint and baseline during the treatment). Multiple logistic regression analyses were performed on the associations between each NPS improvement and neurocognitive change as well as socio-clinico-demographic variables of interest. Results: At endpoint, NPS improvement rates were 76.1%, 70.8%, and 58.1% in CGI-C, NPI, and BPRS, respectively, while MMSE score change was –2.3±3.8. NPS improvement was significantly related to more severe psychotic symptoms at baseline and preserved levels of neurocognition (smaller MMSE score change) among several variables. Conclusions: Our findings suggested that neurocognitive preservation may be associated with attaining optimal benefits from any treatment against NPSs in a longitudinal treatment course of patients with AD. Show more

Keywords: Alzheimer’s disease, antipsychotic, CATIE-AD, neurocognitive impairment, neuropsychiatric symptom

DOI: 10.3233/JAD-180304

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 139-148, 2018

Authors: Jütten, Linda Helena | Mark, Ruth Elaine | Wicherts, Jelte Michiel | Sitskoorn, Margriet Maria

Article Type: Research Article

Abstract: Background: Many psychosocial and behavioral interventions have been developed for informal dementia caregivers. Because existing meta-analyses only focused on a limited number of interventions and outcomes, how effective these interventions are overall and which interventions components are associated with larger effects has yet to be explored. Objective: To provide a comprehensive meta-analysis of the effectiveness of psychosocial and behavioral interventions on burden, depression, anxiety, quality of life, stress, and sense of competence in informal dementia caregivers. In addition, we examined if interventions which utilized more sessions and/or were delivered personally (face-to-face) had larger effect sizes. In …exploratory meta-regressions, we examined seven additional moderators. Methods: The protocol was registered with PROSPERO, number CRD42017062555. We systematically searched the literature to identify controlled trials assessing the effect of psychosocial and behavioral interventions on the six outcome measures, for informal dementia caregivers. We performed six random effects meta-analyses, to assess the pooled effect sizes of the interventions. In addition, we performed separate meta-regressions, for each outcome, for each moderator. Results: The sample consisted of 60 studies. For all outcomes except anxiety, the pooled effects were small and in favor of the intervention group. No moderator was found to systematically predict these effects. There were no indications for publication bias or selection bias based on significance. Conclusion: Overall, the interventions yield significant (small) effects, independent of intervention characteristics. Future research should explore options to enhance the effectiveness of interventions aimed at assisting informal caregivers. Show more

Keywords: Burden, dementia, depression, informal caregivers, interventions, meta-analysis, meta-regression, psychobehavioral, psychosocial

DOI: 10.3233/JAD-180508

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 149-172, 2018

Authors: Ávila-Villanueva, Marina | Maestú, Fernando | Fernández-Blázquez, Miguel A.

Article Type: Research Article

Abstract: Background: Early intervention to prevent, or delay, the transition from healthy cognition to cognitive impairment in older adults is an important goal. In this way, it is critical to find sensitive, reproducible, and early markers to use low cost methods for the detection of that transition. One of those early markers for symptomatic manifestation of AD is subjective cognitive decline (SCD). Objective: To examine the internal consistency of the concept of SCD and to evaluate its clinical significance on the progression through the continuum of AD. Methods: 1,091 cognitively healthy individuals from the Vallecas Project cohort …were followed for three years. Cognitive complaints were systematically collected and analyzed along with clinical data. All participants were classified in three groups at every visit based on specific features of their complaints. Results: Concordance analyses showed a good agreement in longitudinal classification of SCD. The Multi-state Markov Model highlighted a unidirectional transition from the status of no cognitive complaints to SCD. Interestingly, a more severe condition of SCD, namely SCD Plus, showed the highest risk of progression to mild cognitive impairment. Conclusions: The concept of SCD is stable over time when it is operationally defined and consistently assessed. It provides not only a fast identification of individuals at higher risk of future mild cognitive impairment, but also it allows us to track longitudinal trajectories. Show more

Keywords: Aging, Alzheimer’s disease, cognitive symptoms, dementia, mild cognitive impairment, subjective cognitive decline

DOI: 10.3233/JAD-180307

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 173-183, 2018

Authors: Zupanic, Eva | Kåreholt, Ingemar | Norrving, Bo | Secnik, Juraj | von Euler, Mia | Winblad, Bengt | Religa, Dorota | Kramberger, Milica Gregoric | Johnell, Kristina | Eriksdotter, Maria | Garcia-Ptacek, Sara

Article Type: Research Article

Abstract: Background: Previous studies have shown that patients with dementia receive less testing and treatment for stroke. Objectives: Our aim was to investigate hospital management of acute ischemic stroke in patients with and without dementia. Methods: Retrospective analysis of prospectively collected data 2010–2014 from the Swedish national dementia registry (SveDem) and the Swedish national stroke registry (Riksstroke). Patients with dementia who suffered an acute ischemic stroke (AIS) (n  = 1,356) were compared with matched non-dementia AIS patients (n  = 6,755). Outcomes included length of stay in a stroke unit, total length of hospitalization, and utilization of …diagnostic tests and assessments. Results: The median age at stroke onset was 83 years. While patients with dementia were equally likely to be directly admitted to a stroke unit as their non-dementia counterparts, their stroke unit and total hospitalization length were shorter (10.5 versus 11.2 days and 11.6 versus 13.5, respectively, p  < 0.001). Dementia patients were less likely to receive carotid ultrasound (OR 0.36, 95% CI [0.30–0.42]) or undergo assessments by the interdisciplinary team members (physiotherapists, speech therapists, occupational therapists; p  < 0.05 for all adjusted models). However, a similar proportion of patients received CT imaging (97.4% versus 98.6%, p  = 0.001) and a swallowing assessment (90.7% versus 91.8%, p  = 0.218). Conclusions: Patients with dementia who suffer an ischemic stroke have equal access to direct stroke unit care compared to non-dementia patients; however, on average, their stay in a stroke unit and total hospitalization are shorter. Dementia patients are also less likely to receive specific diagnostic tests and assessments by the interdisciplinary stroke team. Show more

Keywords: Cohort studies, dementia, hospital management, ischemic stroke

DOI: 10.3233/JAD-180653

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 185-194, 2018

Authors: Panagaki, Theodora | Gengler, Simon | Hölscher, Christian

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) afflicts more than 46.8 million people worldwide, with a newly diagnosed case every 3 seconds and no remission in the disease progression. The discovery of disease-modifying drugs is now on the summit of the neuropharmacological research priorities. The long-lasting derivatives of the insulinotropic incretin hormones—glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—have repeatedly been shown to cross the blood-brain barrier and counteract an array of deleterious effects across a range of experimental models of neuronal degeneration. Clinical trials for the efficacy of GLP-1 agonists in Alzheimer’s and Parkinson’s diseases have revealed beneficial effects of these anti-diabetic …agents in halting neuronal degeneration progression. Herein, we examine whether the chronic treatment with the novel dual GLP-1/GIP receptor agonist DA-CH3 can restore the cognitive decline and AD-like cerebral pathology of the APPSWE /PS1Δ E9 mouse model at the age of 10 months old. We report that once-a-daily, eight-week intraperitoneal administration of 25 nmol/kg of the novel DA-CH3 dual-incretin analog rescues the spatial acquisition and memory impairments of this murine model that corresponds to the attenuation of the excessive plaque deposition, gliosis and synaptic damage in the APPSWE /PS1Δ E9 brain. The amelioration of the AD-related pathology reflects the resolution of the endoplasmic-reticulum stress and derailed autophagy that both lay downstream of the rectified Akt signaling. Collectively, our findings endorse the beneficial effects of the incretin-based therapeutic approaches for the neurotrophic support of the AD brain and for the first time associate the incretin-induced neuroprotection with the proteostasis machinery in vivo . Show more

Keywords: Alzheimer’s disease, APP/PS1 mouse model, autophagy, ER stress, GLP-1/GIP dual agonist, neurotrophins

DOI: 10.3233/JAD-180584

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 195-218, 2018

Authors: Fiorini, Michele | Bongianni, Matilde | Benedetti, Maria Donata | Monaco, Salvatore | Zanusso, Gianluigi

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) biomarkers are currently included in the diagnostic criteria for Alzheimer’s disease (AD), in particular, decreased concentrations of amyloid-β peptide 1–42 (Aβ42 ) in the CSF, coupled with increased levels of tau and phosphorylated tau proteins, are supportive of AD diagnosis. To date, the quantification of Aβ42 levels with antibody-dependent immunoassay shows a marked variability among different laboratories and is also affected by different pre-analytical factors, suggesting that part of Aβ42 peptides might be aggregated and thus undetected by antibodies. To bypass an antibody-dependent measurement, we determined the Aβ40 and Aβ42 levels by immunoblot. …We analyzed CSF samples from 35 patients with clinical diagnosis of probable AD and from 15 age-matched normal controls; CSF Aβ levels were determined by two different ELISA kits and by immunoblot analysis. Aβ40 levels measured by ELISA were comparable to those obtained by immunoblot, whereas CSF concentrations of Aβ42 measured by ELISA were significantly lower compared to values obtained by immunoblot quantification. Biochemical analysis, following 1D- and 2D-PAGE analysis, showed that the qualitative composition of Aβ peptides in the CSF is similar in AD and controls but different from that of AD brain tissues. Moreover, sedimentation velocity in sucrose gradient of CSF and brain homogenate from AD demonstrated that Aβ42 in CSF is different from Aβ42 in brain in terms of solubility and aggregation state. Show more

Keywords: Aβ1-42, Aβ oligomers, aggregation, Alzheimer’s disease, ELISA

DOI: 10.3233/JAD-180616

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 219-227, 2018

Authors: Fiorenzato, Eleonora | Biundo, Roberta | Cecchin, Diego | Frigo, Anna Chiara | Kim, Jinhee | Weis, Luca | Strafella, Antonio P. | Antonini, Angelo

Article Type: Research Article

Abstract: Background: The pathological processes underlying cognitive impairment in Parkinson’s disease (PD) are heterogeneous and the contribution of cerebral amyloid deposits is poorly defined, particularly in the early stages of the disease. Objective: To investigate regional [18 F]florbetaben binding to amyloid-β (Aβ ) and its contribution to cognitive dysfunction in early stage PD. Methods: A multicenter cohort of 48 PD patients from the Parkinson’s Progression Marker Initiative (PPMI) underwent [18 F]florbetaben positron emission tomography (PET) scanning. Clinical features, including demographic characteristics, motor severity, cerebrospinal fluid (CSF), and cognitive testing were systematically assessed according to the PPMI …study protocol. For the purpose of this study, we analyzed various neuropsychological tests assessing all cognitive functions. Results: There were 10/48 (21%) amyloid positive PD patients (PDAβ +). Increased [18 F]florbetaben uptake in widespread cortical and subcortical regions was associated with poorer performance on global cognition, as assessed by Montreal Cognitive Assessment (MoCA), and impaired performance on Symbol Digit Modality test (SDMT). Further, we found that PDAβ + patients had higher CSF total-tau/Aβ 1 - 42 (p  = 0.001) and phosphorylated-tau/Aβ 1 - 42 in (p  = 0.002) compared to amyloid-negative PD. Conclusion: These findings suggest that multiple disease processes are associated with PD cognitive impairment and amyloid deposits may be observed already in early stages. However, prevalence of amyloid positivity is in the range of literature age-matched control population. Increased cortical and subcortical amyloid is associated with poor performance in attentive-executive domains while cognitive deficits at MoCA and SDMT may identify amyloid-related dysfunction in early PD. Show more

Keywords: Amyloid, cerebrospinal fluid, cognition, cognitive dysfunction, dementia, neuropsychology, Parkinson’s disease, positron emission tomography, synuclein

DOI: 10.3233/JAD-180390

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 229-237, 2018

Authors: Katz, Mindy J. | Wang, Cuiling | Derby, Carol A. | Lipton, Richard B. | Zimmerman, Molly E. | Sliwinski, Martin J. | Rabin, Laura A.

Article Type: Research Article

Abstract: Background: The relation of pre-dementia stages to mortality has not been fully explored. Previous work examining subjective cognitive decline (SCD) and mortality is limited and mixed regarding methods used and consistency of findings. Objective: To examine SCD and mortality in a longitudinal, community-based cohort, using item response theory (IRT) methodology to form a composite SCD measure. Also, to assess whether this relationship was independent of clinical cognitive status. Methods: The Einstein Aging Study is a diverse longitudinal cohort of adults aged ≥70. SCD items were extracted from baseline CERAD questionnaires and a composite score was formed …using IRT methodology. A total of 1,741 participants with complete data were clinically diagnosed as cognitively normal, or as having amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), or dementia. 645 deaths occurred over a period of 8,912 person-years of follow-up. Cox proportional hazard models predicted time to death adjusting for covariates. Results: A one standard deviation unit increase in level of SCD was associated with >20% higher risk of mortality. However, when models were adjusted for clinical cognitive status, the association was no longer significant. Both dementia and aMCI predicted mortality. Furthermore, when analyses focused only on those without cognitive impairment, SCD level did not predict mortality. Conclusions: The association of SCD with mortality may be due to the association of SCD with clinical cognitive status. Thus, SCD may be used as a community-based screen to initially identify those with cognitive impairment who may be at greatest risk for death. Show more

Keywords: Dementia, IRT methodology, mild cognitive impairment, mortality, subjective cognitive decline

DOI: 10.3233/JAD-180335

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 239-248, 2018

Authors: Minn, Yang-Ki | Choi, Seong Hye | Suh, Young Ju | Jeong, Jee Hyang | Kim, Eun-Joo | Kim, Jong Hun | Park, Kyung Won | Park, Moon Ho | Youn, Young Chul | Yoon, Bora | Choi, Seok-Jin | Oh, Youn Kyung | Yoon, Soo Jin

Article Type: Research Article

Abstract: Background: There is a lack of research on the effects of physical activity (PA) on the progression of Alzheimer’s disease (AD). Objectives: We investigated whether PA is associated with progression of dementia and mortality in AD. Methods: In the present study, 934 patients with mild-to-moderate AD were included. PA was evaluated using a questionnaire written by the caregiver. The outcome measures were the Clinical Dementia Rating-Sum of Boxes (CDR-SB), Seoul-Instrumental Activities of Daily Living (S-IADL), Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI), a global composite score of neuropsychological subtests, and mortality. They were evaluated annually and received a maximum …of three follow-up examinations. Results: Between-group differences compared with the no PA group in the change of CDR-SB scores were –0.431 (95% CI = –0.824∼–0.039; p  = 0.031) for the moderate PA group (150–750 minutes per week of moderate intensity PA), and –1.148 (–1.656∼–0.639; p  < 0.001) for the high PA group (>750 minutes per week). As PA increased, there was a significant trend to slow the rate of increase in the CDR-SB, S-IADL, and CGA-NPI scores. The patients with ≥150 minutes per week for each of non-recreational and recreational PAs had a lower risk of mortality compared to those with <150 minutes per week for each of the PAs (hazard ratio 0.22, 95% CI = 0.05∼0.88; p  = 0.033). Conclusion: More PA is associated with slower progression of dementia severity, functional decline, and abnormal behavior, and with a lower risk of mortality in AD. Show more

Keywords: Alzheimer’s disease, dementia, physical activity, progression, mortality

DOI: 10.3233/JAD-180333

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 249-261, 2018

Authors: Medvedev, Alexei E. | Radko, Sergey P. | Yurinskaya, Marina M. | Vinokurov, Maxim G. | Buneeva, Olga A. | Kopylov, Arthur T. | Kozin, Sergey A. | Mitkevich, Vladimir A. | Makarov, Alexander A.

Article Type: Research Article

Abstract: Angiotensin converting enzyme (ACE) is involved in proteolytic processing of the amyloid-β(Aβ) peptide implicated in the development of Alzheimer’s disease (AD) and known products of ACE-based processing of Aβ42 are characterized by reduced aggregability and cytotoxicity. Recently it has been demonstrated that ACE can act as an arginine specific endopeptidase cleaving the N-terminal pentapeptide (Aβ1-5 ) from synthetic Aβ peptide analogues. In the context of proteolytic processing of full length Aβ42 , this suggests possible formation of Aβ6-42 species. The aim of this study was to test a hypothesis that some N-terminally truncated Aβ peptide(s) could retain aggregability …and neurotoxic properties typical for Aβ42 . We have investigated aggregability of two amyloid-β peptides, Aβ6-42 and isoD7-Aβ6-42 , mimicking potential proteolytic products of Aβ42 and isoD7-Aβ42 , and evaluated their effects on the repertoire of brain Aβ binding proteins, and cytotoxicity towards neuroblastoma SH-SY5Y cells. Aggregability of isoD7-Aβ6-42 and Aβ6-42 was higher than that of full-length peptides Aβ42 and isoD7-Aβ42 , while the repertoire of mouse brain Aβ binding proteins dramatically decreased. Aβ6-42 and isoD7-Aβ6-42 exhibited higher neurotoxicity towards SH-SY5Y cells than Aβ42 and isoD7-Aβ42 , respectively. They effectively stimulated production of ROS and NO, and also TNFα secretion by cells. Thus, our results suggest that ACE-dependent processing of full-length Aβs could result in formation of more pathogenic peptides. Show more

Keywords: Aβ6-42 species, Aβ42 , Aβ binding proteins, aggregability, angiotensin converting enzyme, cytotoxicity, proteolytic processing

DOI: 10.3233/JAD-180500

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 263-270, 2018

Authors: Bera, Géraldine | Migliaccio, Raffaella | Michelin, Thibaut | Lamari, Foudil | Ferrieux, Sophie | Nogues, Marie | Bertin, Hugo | Habert, Marie Odile | Dubois, Bruno | Teichmann, Marc | Kas, Aurélie

Article Type: Research Article

Abstract: Semantic variant of primary progressive aphasia (svPPA) is typically associated with non-Alzheimer’s disease (AD) pathology. However, some anatomopathological studies have found AD lesions in those patients. We compared brain perfusion SPECT of 18 svPPA patients with cerebrospinal fluid (CSF) biomarkers indicative of non-AD pathology (svPPA-nonAD) and three svPPA patients with CSF biomarkers indicative of underlying AD (svPPA-AD). All svPPA patients had severe left temporopolar hypoperfusion. SvPPA-nonAD had additional anterior cingulate and mediofrontal hypoperfusion, whereas svPPA-AD had greater left parietal and posterior cingulate involvement. Parietal damage in svPPA constitutes a biomarker for underlying Alzheimer pathology thus refining the classification of this …PPA variant. Show more

Keywords: Alzheimer’s disease, atypical AD, cerebrospinal fluid examination, parietal lobe, semantic variant of primary progressive aphasia, single photon emission computed tomography

DOI: 10.3233/JAD-180087

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 271-280, 2018

Authors: Monacelli, Fiammetta | Pizzonia, Monica | Signori, Alessio | Nencioni, Alessio | Giannotti, Chiara | Minaglia, Cecilia | Granello di Casaleto, Tommaso | Podestà, Silvia | Santolini, Federico | Odetti, Patrizio

Article Type: Research Article

Abstract: Background: Hip fracture is a major health problem and a patient’s biological age, comorbidity, and cognitive vulnerability have an impact on its related outcomes. Length of stay (LOS) for these highly vulnerable patients is rather long and the possible causes have not been clearly identified yet. Objective: We aimed to assess the main clinical factors associated with protracted LOS, focusing on delirium with or without dementia in older age hip fractured patients. Methods: 218 subjects (mean age 86.70±6.18 years), admitted to the Orthogeriatric Unit of the Ospedale Policlinico San Martino (Italy), were recruited. …All patients received physical and comprehensive geriatric assessment. Days to surgery, days from surgery to rehabilitation, and LOS were recorded. In-hospital and three months’ mortality were reported. Results: Prevalent delirium at hospital admission was of 3.1%. 35% of patients developed incident delirium. 56.4% were affected by dementia of Alzheimer-type. In addition, 52% of patients developed delirium superimposed to dementia. Mean LOS was 13.5±4.99 days. Namely, delirium, time to surgery, and complication rate disproportionally affected LOS. The analysis with 3 months mortality, based on cognitive vulnerability profiles, showed how delirium mainly affect short-term mortality in patients with dementia. Conclusion: Our exploratory study originally pointed out the high incidence of delirium superimposed to dementia in orthogeriatric wards and how delirium turns to be a moderator of LOS. The results meet the need for additional research by virtue of a deeper understanding of the impact of delirium and dementia on orthogeriatric clinical management and outcomes. Show more

Keywords: Cognitive vulnerability, dedicated orthogeriatric pathway, hip fracture, length of stay

DOI: 10.3233/JAD-180153

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 281-288, 2018

Authors: Ohtani, Ryo | Nirengi, Shinsuke | Nakamura, Michikazu | Murase, Nagako | Sainouchi, Makoto | Kuwata, Yasuhiro | Takata, Masaki | Masuda, Yuuichi | Kotani, Kazuhiko | Sakane, Naoki

Article Type: Research Article

Abstract: Background: High-density lipoprotein (HDL) containing apolipoprotein A-I is associated with the pathogenesis of Alzheimer’s disease (AD). HDL particle size is modified in the presence of pathological conditions, while the significance of the HDL particle size remains controversial. Objective: The aim of this study was to investigate the HDL lipoprotein subclasses in mild cognitive impairment (MCI) and AD. Methods: This cross-sectional study included 20 AD patients, 17 MCI patients, and 17 age-matched controls without cognitive impairment, selected from the database of the Study of Outcome and aPolipoproteins in Dementia (STOP-Dementia) registry. The diagnoses of …AD and MCI were performed by expert neurologists according to the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition criteria. Serum HDL subclasses were measured by electrophoretic separation of lipoproteins using the Lipoprint System. The neutrophil-lymphocyte ratio (NLR), a marker of inflammation, was calculated by dividing the neutrophil count by the lymphocyte count. Results: Small-sized HDL particle levels in the MCI group were significantly higher than in the control group, although there was no difference in serum HDL-cholesterol levels between MCI and control groups. NLR in the MCI group was higher than in the control group, but this difference was non-significant (p  = 0.09). There was no difference in HDL subclasses or NLR between the AD and control groups. Conclusion: These findings suggest that HDL subclasses might be associated with the development of MCI. Show more

Keywords: Alzheimer’s disease, HDL subfraction, high-density lipoprotein, inflammation, mild cognitive impairment

DOI: 10.3233/JAD-180135

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 289-296, 2018

Authors: Cui, Chendi | Sekikawa, Akira | Kuller, Lewis H. | Lopez, Oscar L. | Newman, Anne B. | Kuipers, Allison L. | Mackey, Rachel H.

Article Type: Research Article

Abstract: Cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. High cfPWV is related to white matter hyperintensities and brain amyloid deposition, and to cognitive decline, but it is unclear whether cfPWV independently predicts incident dementia. Therefore, we tested the hypothesis that cfPWV predicts incident dementia in older adults, independent of potential confounders. The Cardiovascular Health Study Cognition Study followed 532 non-demented older adults with …annual cognitive exams from 1998-99 through 2013. CfPWV was measured on 356 (mean age = 78, 59% women) between 1996–2000. Over 15 years, 212 (59.6%) developed dementia (median time from cfPWV measurement = 4 years). In age and sex-adjusted Cox models, cfPWV was significantly associated with increased risk of dementia, but systolic blood pressure, mean arterial pressure and pulse pressure were not. CfPWV (transformed as – 1/cfPWV) remained significantly associated with dementia risk when further adjusted for education, race, APOE ɛ 4, diabetes, body mass index, mean arterial pressure, and anti-hypertensive medication (hazard ratio = 1.60, 95% CI = 1.02, 2.51). Results were similar when further adjusted for baseline global cognition, subclinical brain measures, and coronary artery calcification. Finally, higher cfPWV was related to lower physical activity intensity and higher systolic blood pressure, heart rate, and waist circumference measured 5 years prior. An important unanswered question is whether interventions to slow arterial stiffening can reduce the risk of dementia. Show more

Keywords: Dementia, pulse wave velocity, risk factors, vascular stiffness

DOI: 10.3233/JAD-180449

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 297-306, 2018

Authors: Baran, Timothy M. | Lin, Feng Vankee | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Some individuals, called Supernormals (SN), maintain excellent memory in old age. While brain structural and functional integrity in SN seem to be aging-resistant, their amyloidosis and neural injury status has not been well studied. Objective: The goal of this study was to compare cortical amyloid deposition and glucose metabolism between SN and older adults with normal cognition (NC), amnestic mild cognitive impairment (MCI), and Alzheimer’s disease (AD). Methods: Subjects from the ADNI database were included if they received T1-weighted MRI, amyloid PET, FDG-PET, and cognitive testing within a 6-month period, yielding 27 AD, 69 MCI, …172 NC, and 122 SN. PET standardized uptake value ratios (SUVrs) were calculated for the whole cortex and 68 regions of interest, with whole cerebellum serving as reference. Results: SN had lower whole cortex amyloid than MCI, and higher glucose metabolism than all others. Regional analysis revealed that amyloid burden and glucose metabolism in the right isthmus cingulate cortex differed in SN compared to others, while SN glucose metabolism also differed from others in several frontal and temporal regions. Conclusion: Preserved cortical glucose metabolism, and lower levels of amyloidosis and glucose hypometabolism in the right isthmus cingulate cortex, contributes to the Supernormal phenomenon. These findings may be informative for development of early screening biomarkers and therapeutic targets for modification of cognitive trajectories. Show more

Keywords: Amyloid-β, glucose metabolism, magnetic resonance imaging, positron emission tomography, successful cognitive aging, supernormal

DOI: 10.3233/JAD-180360

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 307-318, 2018

Authors: Nakajima, Madoka | Miyajima, Masakazu | Ogino, Ikuko | Akiba, Chihiro | Kawamura, Kaito | Kamohara, Chihiro | Fusegi, Keiko | Harada, Yoshinao | Hara, Takeshi | Sugano, Hidenori | Tange, Yuichi | Karagiozov, Kostadin | Kasuga, Kensaku | Ikeuchi, Takeshi | Tokuda, Takahiko | Arai, Hajime

Article Type: Research Article

Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) is commonly treated by cerebrospinal fluid (CSF) shunting. However, the long-term efficacy of shunt intervention in the presence of comorbid Alzheimer’s disease (AD) pathology is debated. Objective: To identify AD-associated CSF biomarkers predictive of shunting surgery outcomes in patients with iNPH. Methods: Preoperative levels of total and phosphorylated Tau (p-Tau) were measured in 40 patients with iNPH divided into low (<30 pg/mL) and high (≥30 pg/mL) p-Tau groups and followed up for three years after lumboperitoneal shunting. The modified Rankin Scale (mRS), Mini-Mental State Examination (MMSE), Frontal …Assessment Battery, and iNPH Grading Scale scores were compared between the age-adjusted low (n  = 24; mean age 75.7 years [SD 5.3]) and high (n  = 11; mean age 76.0 years [SD 5.6]) p-Tau groups. Results: Cognitive function improved early in the low p-Tau group and was maintained thereafter (p  = 0.005). In contrast, the high p-Tau group showed a gradual decline to baseline levels by the third postoperative year (p  = 0.040). Although the p-Tau concentration did not correlate with the preoperative MMSE score, a negative correlation appeared and strengthened during follow-up (R2  = 0.352, p  < 0.001). Furthermore, the low p-Tau group showed rapid and sustained mRS grade improvement, whereas mRS performance gradually declined in the high p-Tau group. Conclusions: Preoperative CSF p-Tau concentration predicted some aspects of cognitive function after shunt intervention in patients with iNPH. The therapeutic effects of shunt treatment were shorter-lasting in patients with coexisting AD pathology. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid shunt, normal pressure hydrocephalus, phosphorylation, prognosis, tau proteins

DOI: 10.3233/JAD-180557

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 319-331, 2018

Authors: Gao, Yuan | Liu, En-Jie | Wang, Wei-Jin | Wang, Ya-Li | Li, Xiao-Guang | Wang, Xin | Li, Shi-Hong | Zhang, Shu-Juan | Li, Meng-Zhu | Zhou, Qiu-Zhi | Long, Xiao-Bing | Zhang, Hua-Qiu | Wang, Jian-Zhi

Article Type: Research Article

Abstract: Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer’s disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased …pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation. Show more

Keywords: Alzheimer’s disease, amyloid-β, cAMP response element-binding protein, microglia, protein kinase A

DOI: 10.3233/JAD-180286

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 333-345, 2018

Authors: Zammit, Andrea R. | Hall, Charles B. | Katz, Mindy J. | Muniz-Terrera, Graciela | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Identifying preclinical Alzheimer’s disease (AD) is an important step toward developing approaches to early treatment and dementia prevention. We applied latent class analysis (LCA) to 10 baseline neuropsychological assessments for 1,345 participants from Einstein Aging Study. Time-to-event models for all-cause dementia and AD were run examining events in 4-year intervals. Five classes were identified: Mixed-Domain Impairment (n = 107), Memory-Specific Impairment (n = 457), Average (n = 539), Frontal Impairment (n = 118), and Superior Cognition (n = 124). Compared to the Average class, the Mixed-Domain Impairment and Memory-Specific Impairment classes were at higher risk …of incident all-cause dementia and AD in the first 4 years from baseline, while the Frontal Impairment class was associated with higher risk between 4 and 8 years of follow-up. LCA identified classes which differ in cross-sectional cognitive patterns and in risk of dementia over specific follow-up intervals. Show more

Keywords: All-cause dementia, Alzheimer’s disease, cognitive aging, cognitive subtypes, heterogeneity, individual differences, neuropsychology

DOI: 10.3233/JAD-180604

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 347-357, 2018

Authors: Schlenzig, Dagmar | Cynis, Holger | Hartlage-Rübsamen, Maike | Zeitschel, Ulrike | Menge, Katja | Fothe, Anja | Ramsbeck, Daniel | Spahn, Claudia | Wermann, Michael | Roßner, Steffen | Buchholz, Mirko | Schilling, Stephan | Demuth, Hans-Ulrich

Article Type: Research Article

Abstract: The formation of amyloid-β (Aβ) peptides is causally involved in the development of Alzheimer’s disease (AD). A significant proportion of deposited Aβ is N-terminally truncated and modified at the N-terminus by a pGlu-residue (pGlu-Aβ). These forms show enhanced neurotoxicity compared to full-length Aβ. Although the truncation may occur by aminopeptidases after formation of Aβ, recently discovered processing pathways of amyloid-β protein precursor (AβPP) by proteases such as meprin β may also be involved. Here, we assessed a role of meprin β in forming Aβ3 -40/42 , which is the precursor of pGlu-Aβ3 -40/42 generated by glutaminyl cyclase (QC). Similar …to QC, meprin β mRNA is significantly upregulated in postmortem brain from AD patients. A histochemical analysis supports the presence of meprin β in neurons and astrocytes in the vicinity of pGlu-Aβ containing deposits. Cleavage of AβPP-derived peptides by meprin β in vitro results in peptides Aβ1 -x , Aβ2 -x , and Aβ3 -x . The formation of N-truncated Aβ by meprin β was also corroborated in cell culture. A subset of the generated peptides was converted into pGlu-Aβ3 -40 by an addition of glutaminyl cyclase, supporting the preceding formation of Aβ3 -40 . Further analysis of the meprin β cleavage revealed a yet unknown dipeptidyl-peptidase–like activity specific for the N-terminus of Aβ1 -x . Thus, our data suggest that meprin β contributes to the formation of N-truncated Aβ by endopeptidase and exopeptidase activity to generate the substrate for QC-catalyzed pGlu-Aβ formation. Show more

Keywords: Amyloid-β, dipeptidyl peptidase, meprin β, secretase

DOI: 10.3233/JAD-171183

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 359-375, 2018

Authors: Mendiratta, Priya | Wei, Jeanne Y. | Dayama, Neeraj | Li, Xiaocong

Article Type: Research Article

Abstract: Background: Patients with Down syndrome (DS) often survive into adulthood. Relatively little information is currently available regarding hospitalization outcomes among mature, older adults with DS. Objective: To identify risk factors associated with hospital mortality rates and increased costs for hospitalized older adults with DS. Methods: Data on hospitalized older adults with DS (≥65 years) were identified from the Nationwide Inpatient Sample database (6) from 2002 through 2012. Multivariate analyses were performed to evaluate risk factors associated with hospital mortality and hospitalization cost in these patients. Results: A total of 2,134 older adults with DS …were identified. A temporal increase over the 11-year period was observed in the number of older adults with DS who were hospitalized (trend p < 0.0001). However, the hospital mortality rate and post-hospital discharge to skilled nursing facilities have decreased during the same time period. Risk factors associated with increased hospital mortality included advanced age (70–79 years), female gender, admissions in the western United States, and presence of comorbid conditions (ischemic heart disease, Alzheimer’s disease, and cerebrovascular accident). The mean cost was $18,241 (SD $56,105) over the 11-year period. However, no significant temporal changes in costs were noted (trend p = 0.14). Conclusions: The number of hospitalized elderly Americans with DS has increased over the 11-year period. However, hospital mortality and discharge to skilled nursing facilities have decreased during the same time period. Several demographic and co-morbid factors are associated with increased mortality. No significant differences in temporal trends in costs were noted. Show more

Keywords: Down syndrome, elderly, outcomes

DOI: 10.3233/JAD-171067

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 377-386, 2018

Authors: Sarycheva, Tatyana | Taipale, Heidi | Lavikainen, Piia | Tiihonen, Jari | Tanskanen, Antti | Hartikainen, Sirpa | Tolppanen, Anna-Maija

Article Type: Research Article

Abstract: Background: Although antiepileptic drugs (AEDs) have a potential for adverse drug reactions in older populations, little is known about their use in relation to Alzheimer’s disease (AD) diagnosis. Objectives: In this study, we investigated the incidence and prevalence of AED use in relation to AD diagnosis. Methods: The MEDALZ–study includes all Finnish persons who received clinically verified AD diagnoses (n  = 70,718) during 2005–2011 and a matched comparison cohort without AD (n  = 70,718). AD diagnoses were identified from the Special Reimbursement Register. We used the Prescription Register to identify dispensed AEDs. Incident AED users were identified with …a one-year washout period 9-10 years before AD diagnosis, and incidence rates per 100 person-years were calculated for each six-month period from nine years before to five years after AD diagnosis. Prevalence was assessed as proportion using AEDs during each six-month time period for incident use. Results: Persons with AD were more likely to use AEDs during the study period (4.3%) than persons without AD (3.2%). The incidence and prevalence of AED use was higher among persons with AD and increased around the time of AD diagnosis. Epilepsy diagnoses did not explain these differences. Persons with AD were more likely to use older AEDs. Conclusion: Our study highlights the need to balance effective symptom control with the possible risks of treatment. Show more

Keywords: Alzheimer’s disease, antiepileptic drugs, dementia, incidence, prevalence

DOI: 10.3233/JAD-180594

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 387-395, 2018

Authors: McCade, Donna L. | Guastella, Adam J. | Chen, Nigel T.M. | Lewis, Simon J.G. | Naismith, Sharon L.

Article Type: Research Article

Abstract: Background: Research suggests that deficits in emotion recognition are evident in individuals with amnestic mild cognitive impairment (aMCI), a group ‘at risk’ of developing dementia. The mechanisms underlying this deficit, however, are unclear. Objective: In this study, we sought to determine whether there are alterations in the way in which individuals with MCI visually explore emotional facial stimuli. Methods: Eighteen healthy older controls (mean age = 64.6 years) and 32 individuals with MCI were recruited including 18 with the non-amnestic multiple domain (naMCI-md) subtype (mean age = 63.8 years) and 14 with the amnestic multiple domain (aMCI-md) subtype (mean age = 67.9 …years). All participants were given a novel eye-tracking paradigm to investigate eye gaze while viewing images of emotional faces on a computer screen. Results: Analyses of eye gaze revealed no significant difference in the percentage of time that groups spent fixating on facial and peripheral facial regions when viewing emotional faces. All participants showed a relative preference for the eye region of faces relative to all other regions. Individuals with aMCI-md were found to be less accurate than controls and naMCI-md on emotion recognition measures. For naMCI-md individuals, significant relationships were found between efficiencies in visual scanning and increased fixation time on the eye region. Conclusions: Visual processing strategies adopted by aMCI-md individuals when exploring emotional faces do not significantly differ from those of healthy controls or naMCI-md individuals. This suggests that impaired facial emotion recognition in aMCI-md is not likely accounted for by visual processing differences, but rather may reflect an eroded ability to extract meaningful cues from the eye region. Show more

Keywords: Dementia, emotion recognition, eye tracking, mild cognitive impairment

DOI: 10.3233/JAD-170175

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 397-405, 2018

Authors: Wirth, Klaus J.

Article Type: Research Article

Abstract: Background: Cerebral hypoperfusion and degeneration of the noradrenergic locus coeruleus (LC) occur early in Alzheimer’s disease (AD). Cerebral blood vessels are densely innervated by noradrenergic projections from the LC suggesting a functional role for the regulation of cerebral blood flow (CBF). Experimental LC stimulation, however, has provided no clarity as decreases or increases in CBF were reported from different experimental settings and investigators. Objective: To find out with pharmacological methods whether endogenously released norepinephrine (NE) increases or decreases carotid artery blood flow (CABF) in anesthetized pigs by investigating the effect of centrally acting alpha-2 adrenergic drugs, which increase …(atipamezole) or decrease (xylazine) NE in the brain. Methods: CABF was measured by a Doppler-flow probe placed around the left carotid artery in pentobarbital anesthetized young pigs. Results: Neither current antihypertensive drugs nor pharmacological stimulation of dopamine, histamine, serotonin or acetylcholine receptors changed CABF. The alpha-2 adrenergic-receptor agonist xylazine decreased, while the antagonist atipamezole raised CABF. This rise was abolished by a combined treatment with endothelial NO-synthase inhibitor Nω -Nitro-L-arginine methyl ester (L-NAME) and the non-selective β-receptor antagonist propranolol. Propranolol alone did not decrease CABF in contrast to L-NAME but decreased CABF after L-NAME, surprisingly. Conclusion: Pharmacological evidence suggests that NE released in the brain of anesthetized pigs raises CABF involving β-adrenergic mechanisms and nitric oxide. If in awake humans NE released from the LC had vasodilator effects early LC degeneration could be involved in early cerebral hypoperfusion of AD. Moreover, a cerebral adrenergic vascular innervation deficit, possibly resulting from LC degeneration, and systemic endothelial dysfunction together may act synergistically to reduce CBF. Show more

Keywords: Alpha-2 adrenergic drugs, Alzheimer’s disease, atipamezole, carotid artery blood flow, cerebral blood flow, cerebral hypoperfusion, degeneration, locus coeruleus, pigs, propranolol, xylazine

DOI: 10.3233/JAD-180340

Citation: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 407-419, 2018