Journal of Alzheimer's Disease - Volume 64, issue 4

Authors: Baiardi, Simone | Capellari, Sabina | Bartoletti Stella, Anna | Parchi, Piero

Article Type: Review Article

Abstract: The introduction of prion RT-QuIC, an ultrasensitive specific assay for the in vivo detection of the abnormal prion protein, has significantly increased the potential for an early and accurate clinical diagnosis of Creutzfeldt-Jakob disease (CJD). However, in the clinical setting, the early identification of patients with possible CJD is often challenging. Indeed, CJD patients may present with isolated symptoms that remain the only clinical manifestation for some time, or with neurological syndromes atypical for CJD. To enhance awareness of unusual disease presentations and promote earlier diagnosis, we reviewed the entire spectrum of atypical early manifestations of CJD, mainly reported …to date as case descriptions or small case series. They included sensory either visual or auditory disturbances, seizures, isolated psychiatric manifestations, atypical parkinsonian syndromes (corticobasal syndrome, progressive supranuclear palsy-like), pseudobulbar syndrome, isolated involuntary movements (dystonia, myoclonus, chorea, blepharospasm), acute or subacute onsets mimicking a stroke, isolated aphasia, and neuropathy. Since CJD is a rare disease and its clinical course rapidly progressive, an in-depth understanding and awareness of early clinical features are mandatory to enhance the overall diagnostic accuracy in its very early stages and to recruit optimal candidates for future therapeutic trials. Show more

Keywords: Clinical phenotype, Creutzfeldt-Jakob disease, early diagnosis, Heidenhain variant, human prions, movement disorders, neurodegenerative dementia, seizures

DOI: 10.3233/JAD-180123

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1051-1065, 2018

Authors: Schwab, Nicole | Hazrati, Lili-Naz

Article Type: Review Article

Abstract: Chronic traumatic encephalopathy (CTE) is considered to be a progressive neurodegenerative disease caused by mild traumatic brain injury (mTBI). Recently there has been a significant amount of media attention surrounding the commonness of CTE in professional athletes, particularly American football, based on several postmortem case series. However, despite the persuasive claims made by the media about CTE, research on the disease and the effects of mTBI in general remain in its infancy. Commonly cited case series studying CTE are limited by methodological biases, pathological inconsistencies, insufficient clinical data, and a reliance on inherently biased postmortem data. These case series do …not allow for the collection of any epidemiological data and are not representative of the general population. The exaggerated assumptions and assertions taken from these studies run the risk of creating a self-fulfilling prophecy for individuals who believe they are at risk and have the potential to negatively influence sports-related policymaking. This review outlines the status and limitations of recent CTE case series and calls for future prospective, longitudinal studies to further characterize the pathological and clinical hallmarks of CTE. Show more

Keywords: Athletic injury, chronic traumatic encephalopathy, concussion, dementia, neurodegeneration, tauopathies, traumatic brain injury

DOI: 10.3233/JAD-180373

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1067-1076, 2018

Authors: Beam, Christopher R. | Kaneshiro, Cody | Jang, Jung Yun | Reynolds, Chandra A. | Pedersen, Nancy L. | Gatz, Margaret

Article Type: Short Communication

Abstract: In the following brief report, we examined gender differences in incidence rates of any dementia, Alzheimer’s disease (AD) alone, and non-Alzheimer’s dementia alone in 16,926 women and men in the Swedish Twin Registry aged 65+. Dementia diagnoses were based on clinical workup and national health registry linkage. Incidence rates of any dementia and AD were greater in women than men, with any dementia rates diverging after age 85 and AD rates diverging around 80. This pattern is consistent with women’s survival to older ages compared to men. These findings are similar to incidence rates reported in other Swedish samples.

Keywords: Alzheimer’s disease, any dementia, gender differences, incidence, Swedish Twin Registry

DOI: 10.3233/JAD-180141

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1077-1083, 2018

Authors: Rocha, Natalia P. | Toledo, Andre | Corgosinho, Laiane T.S. | de Souza, Leonardo C. | Guimarães, Henrique C. | Resende, Elisa P.F. | Braz, Nayara F.T. | Gomes, Karina B. | Simoes e Silva, Ana C. | Caramelli, Paulo | Teixeira, Antonio L.

Article Type: Short Communication

Abstract: This study was designed to determine whether the levels of renin-angiotensin system (RAS) components are associated with Alzheimer’s disease (AD) pathology. Cerebrospinal fluid levels of Angiotensin (Ang) II, Ang-(1-7), angiotensin-converting enzyme (ACE), ACE2, Amyloid-β (Aβ)40 , Aβ42, total tau (hTau), and phospho-tau (pTau) were measured in 18 patients with AD and 10 controls. Patients with AD presented decreased levels of ACE when compared with controls. We found a significant positive correlation between ACE and Aβ42 levels among patients. Our results strengthen the hypothesis that ACE is associated with Aβ pathology in AD.

Keywords: Alzheimer’s disease, amyloid-beta, angiotensin-converting enzyme, biomarkers, renin-angiotensin system

DOI: 10.3233/JAD-180282

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1085-1090, 2018

Authors: Thyrian, Jochen René | Hertel, Johannes | Schulze, Lara N. | Dörr, Marcus | Prüss, Harald | Hempel, Petra | Bimmler, Marion | Kunze, Rudolf | Grabe, Hans Jörgen | Teipel, Stefan | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. Objective: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α 1-adrenergic receptors (α 1-AR-agAAB) and agABB directed against β 2-adrenergic receptors (β 2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. Methods: Blood samples and …data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. Results: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α 1-AR-agAAB and n = 21 (22%) β 2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α 1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. Discussion: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α 1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB. Show more

Keywords: Antibodies, biomarker, immunoadsorption, prevalence, primary care

DOI: 10.3233/JAD-171096

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1091-1097, 2018

Authors: Casamitjana, Adrià | Petrone, Paula | Tucholka, Alan | Falcon, Carles | Skouras, Stavros | Molinuevo, José Luis | Vilaplana, Verónica | Gispert, Juan Domingo | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: The identification of healthy individuals harboring amyloid pathology represents one important challenge for secondary prevention clinical trials in Alzheimer’s disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60% of unnecessary CSF/PET tests and to reduce 47% of …the cost of recruitment. This recruitment strategy capitalizes on available MR scans to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for preclinical AD screening. This protocol could foster the development of secondary prevention strategies for AD. Show more

Keywords: Amyloid pathology, clinical trial, machine learning, preclinical Alzheimer’s disease, screening, secondaryprevention

DOI: 10.3233/JAD-180299

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1099-1112, 2018

Authors: Renard, Dimitri | Tatu, Lavinia | Collombier, Laurent | Wacongne, Anne | Ayrignac, Xavier | Charif, Mahmoud | Boukriche, Yassine | Chiper, Laura | Fourcade, Genevieve | Azakri, Souhayla | Gaillard, Nicolas | Mercier, Erick | Lehmann, Sylvain | Thouvenot, Eric

Article Type: Research Article

Abstract: Background: Cerebral amyloid angiopathy (CAA) can be associated with primary vasculitis of small/medium-sized leptomeningeal and cortical arteries, called CAA-related inflammation (CAA-ri). Objective: To compare hemorrhagic and diffusion-weighted imaging (DWI) MRI features in CAA and CAA-ri. Methods: We prospectively scored in a consecutive CAA and CAA-ri cohort: presence/number of chronic intracerebral hemorrhage (ICH), cerebral microbleeds (CMB), and cortical superficial siderosis (CSS) on initial T2*-weighted imaging, and DWI lesions on both initial and follow-up imaging. In a subgroup, ApoE, CSF, and 18F-florbetaben-positron emission tomography (FBB-PET) were also analyzed. Results: In CAA-ri, CMB presence was more frequent …(100% versus 40%, p < 0.001) and CMB numbers higher (mean 137 versus 8, p < 0.001). No difference was observed for chronic ICH or CSS. DWI lesions were more frequent in acute compared to chronic CAA-ri (p = 0.025), whereas no such difference was observed between acute and chronic CAA (p = 0.18). Both ApoE4 (genotyping available in 22 CAA-ri and 48 CAA patients) carriers and homozygosity were more frequent in CAA-ri (48% versus 19% [p = 0.014] and 32% versus 2% [p < 0.001] respectively). CSF biomarker analyses (performed in 20 CAA-ri and 45 CAA patients) showed lower Aβ 42 levels in CAA-ri compared to CAA (median 312 versus 422 pg/mL, p = 0.0032). FBB-PET (performed in 11 CAA-ri and 20 CAA patients) showed higher standardized uptake value ratios in CAA-ri compared with CAA, only significant when the pons was used as reference (p = 0.037). Conclusion: Compared to CAA, CAA-ri was associated with higher CMB numbers, more frequent ApoE4 carriers and homozygotes, lower CSF Aβ 42 levels, and more severe amyloid load on FBB-PET. Show more

Keywords: Amyloid imaging, apolipoprotein E genotype, cerebral amyloid angiopathy, cerebral amyloid angiopathy-related inflammation, cerebral microbleeds, cerebrospinal fluid, florbetaben, intracerebral hemorrhage, positron emission tomography

DOI: 10.3233/JAD-180269

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1113-1121, 2018

Authors: Mariani, Elena | Chattat, Rabih | Ottoboni, Giovanni | Koopmans, Raymond | Vernooij-Dassen, Myrra | Engels, Yvonne

Article Type: Research Article

Abstract: Background: Shared decision-making (SDM) can be a way for staff to adopt international recommendations advocating the involvement of nursing home residents and their family members in care planning and the development of personalized care plans. Objective: The main aim was to analyze the effects of training nursing home staff in the implementation of SDM on agreement of residents’ ‘life-and-care plans’ with the recommendations (primary outcome) and on family caregivers’ quality of life and sense of competence, and staff’s job satisfaction (secondary outcomes). Methods: In the intervention condition, staff attended a training program on the use of …SDM with residents and family caregivers in the care planning process. In the control condition, care planning as usual took place. For the primary outcome, in-depth qualitative and quantitative analyses of the care plans were performed. Multivariate Permutation Tests were applied to assess the impact on secondary outcomes. Results: Forty-nine residents and family caregivers and 34 professionals were involved. Overall, many of the care plans developed during the intervention showed a high level of agreement with the care planning recommendations. Both Italian and Dutch care plans showed improvement in the number of clear problem statements (p < 0.001). In Italy, significant improvements (p < 0.05) were also found regarding specific care objectives, documentation of objectives met, and of residents and families’ involvement. No impact was found on secondary outcomes. Conclusion: The involvement of residents and family caregivers in care planning contributed to an improvement of the residents’ care plans, but it did not have an effect on family caregivers and staff outcomes. Show more

Keywords: Care planning policy, care planning regulations, care plans, dementia residents, elderly residents, family caregivers, nursing homes, shared decision-making

DOI: 10.3233/JAD-180279

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1123-1135, 2018

Authors: Whitson, Heather E. | Potter, Guy G. | Feld, Jody A. | Plassman, Brenda L. | Reynolds, Kelly | Sloane, Richard | Welsh-Bohmer, Kathleen A.

Article Type: Research Article

Abstract: Background: Dual-task paradigms, in which an individual performs tasks separately and then concurrently, often demonstrate that people with neurodegenerative disorders experience more dual-task interference, defined as worse performance in the dual-task condition compared to the single-task condition. Objective: To examine how gait-cognition dual-task performance differs between cognitively normal older adults with and without an APOE ɛ 4 allele. Methods: Twenty-nine individuals ages 60 to 72 with normal cognition completed a dual-task protocol in which walking and cognitive tasks (executive function, memory) were performed separately and concurrently. Fourteen participants carried APOE ɛ 4 alleles (ɛ 3/ɛ 4 …or ɛ 2/ɛ 4); fifteen had APOE genotypes (ɛ 2/ɛ 2, ɛ 2/ɛ 3, or ɛ 3/ɛ 3) associated with lower risk of Alzheimer’s disease (AD). Results: The two risk groups did not differ by age, sex, race, education, or gait or cognitive measures under single-task conditions. Compared to low risk participants, APOE ɛ 4 carriers tended to exhibit greater dual-task interference. Both the memory and executive function tasks resulted in dual-task interference on gait, but effect sizes for a group difference were larger when the cognitive task was executive function. In the dual-task protocol that combined walking and the executive function task, effect sizes for group difference in gait interference were larger (0.62– 0.70) than for cognitive interference (0.45– 0.47). Discussion: Dual-task paradigms may reveal subtle changes in brain function in asymptomatic individuals at heightened risk of AD. Show more

Keywords: Aging brain, cognitive performance, cognitive reserve, dementia, diagnosis, early detection, motor interference, phenotype, risk, stress test

DOI: 10.3233/JAD-180016

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1137-1148, 2018

Authors: Ni, Hua | Xu, Min | Zhan, Gui-Lai | Fan, Yu | Zhou, Hejiang | Jiang, Hong-Yan | Lu, Wei-Hong | Tan, Liwen | Zhang, Deng-Feng | Yao, Yong-Gang | Zhang, Chen

Article Type: Research Article

Abstract: Depression is one of the most frequent psychiatric symptoms observed in people during the development of Alzheimer’s disease (AD). We hypothesized that genetic factors conferring risk of depression might affect AD development. In this study, we screened 31 genes, which were located in 19 risk loci for major depressive disorder (MDD) identified by two recent large genome-wide association studies (GWAS), in AD patients at the genomic and transcriptomic levels. Association analysis of common variants was performed by using summary statistics of the International Genomics of Alzheimer’s Project (IGAP), and association analysis of rare variants was conducted by sequencing the entire …coding region of the 31 MDD risk genes in 107 Han Chinese patients with early-onset and/or familial AD. We also quantified the mRNA expression alterations of these MDD risk genes in brain tissues of AD patients and AD mouse models, followed by protein-protein interaction network prediction to show their potential effects in AD pathways. We found that common and rare variants of L3MBTL2 were significantly associated with AD. mRNA expression levels of 18 MDD risk genes, in particular SORCS3 and OAT , were differentially expressed in AD brain tissues. 13 MDD risk genes were predicted to physically interact with core AD genes. The involvement of HACE1 , NEGR1 , and SLC6A15 in AD was supported by convergent lines of evidence. Taken together, our results showed that MDD risk genes might play an active role in AD pathology and supported the notion that depression might be the “common cold” of psychiatry. Show more

Keywords: Alzheimer’s disease, depression, genome-wide association studies, genomics, transcriptomics

DOI: 10.3233/JAD-180276

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1149-1161, 2018

Authors: Liu, Ning | Yu, Zhanyang | Xun, Yu | Shu, Pan | Yue, Yiwei | Yuan, Shishan | Jiang, Yinghua | Huang, Zixuan | Yang, Xiaoping | Feng, Xing | Xiang, Shuanglin | Wang, Xiaoying

Article Type: Research Article

Abstract: Neuroglobin (Ngb) has been reported to be increased in early and moderately advanced Alzheimer’s disease (AD) stages but declined in the severe stage. However, its regulatory mechanisms and pathophysiological roles in the disease remain to be defined. In this study, we found that Ngb expression was significantly upregulated by low dose Aβ25–35 , the neurotoxic fragment of Aβ1 - 40 and Aβ1 - 42 , but was not further increased by a higher dose of Aβ25–35 . Mutation analysis and supershift assay demonstrated that transcription factor Nuclear Factor κ B (NFκ B), κ B2 and κ B3 sites located …in mouse Ngb promoter region were involved in dynamic regulation of Ngb expression in response to different doses of Aβ25–35 stimulation. In addition, we found that suppression of endogenous Ngb expression exacerbated Aβ25–35 -induced neuronal cell death and mitochondrial dysfunction. Our results indicate that endogenous Ngb expression may be upregulated by low dose Aβ25–35, which is responsible for protecting against Aβ25–35 -mediated neurotoxicity. These experimental findings suggest that upregulation of endogenous Ngb expression might be an effective intervention approach for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, mitochondria, neuroglobin, neurotoxicity, NFκB

DOI: 10.3233/JAD-180163

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1163-1174, 2018

Authors: Smailagic, Nadja | Lafortune, Louise | Kelly, Sarah | Hyde, Chris | Brayne, Carol

Article Type: Research Article

Abstract: Background: A previous Cochrane systematic review concluded there is insufficient evidence to support the routine use of 18 F-FDG PET in clinical practice in people with mild cognitive impairment (MCI). Objectives: To update the evidence and reassess the accuracy of 18 F-FDG-PET for detecting people with MCI at baseline who would clinically convert to Alzheimer’s disease (AD) dementia at follow-up. Methods: A systematic review including comprehensive search of electronic databases from January 2013 to July 2017, to update original searches (1999 to 2013). All key review steps, including quality assessment using QUADAS 2, were performed independently …and blindly by two review authors. Meta-analysis could not be conducted due to heterogeneity across studies. Results: When all included studies were examined across all semi-quantitative and quantitative metrics, exploratory analysis for conversion of MCI to AD dementia (n = 24) showed highly variable accuracy; half the studies failed to meet four or more of the seven sets of QUADAS 2 criteria. Variable accuracy for all metrics was also found across eleven newly included studies published in the last 5 years (range: sensitivity 56–100%, specificity 24–100%). The most consistently high sensitivity and specificity values (approximately ≥80%) were reported for the sc-SPM (single case statistical parametric mapping) metric in 6 out of 8 studies. Conclusion: Systematic and comprehensive assessment of studies of 18 FDG-PET for prediction of conversion from MCI to AD dementia reveals many studies have methodological limitations according to Cochrane diagnostic test accuracy gold standards, and shows accuracy remains highly variable, including in the most recent studies. There is some evidence, however, of higher and more consistent accuracy in studies using computer aided metrics, such as sc-SPM, in specialized clinical settings. Robust, methodologically sound prospective longitudinal cohort studies with long (≥5 years) follow-up, larger consecutive samples, and defined baseline threshold(s) are needed to test these promising results. Further evidence of the clinical validity and utility of 18 F-FDG PET in people with MCI is needed. Show more

Keywords: Accuracy, Alzheimer’s disease dementia, conversion, 18F-FDG PET, mild cognitive impairment, test predictive value

DOI: 10.3233/JAD-171125

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1175-1194, 2018

Authors: Lamartinière, Yordenca | Boucau, Marie-Christine | Dehouck, Lucie | Krohn, Markus | Pahnke, Jens | Candela, Pietra | Gosselet, Fabien | Fenart, Laurence

Article Type: Research Article

Abstract: The role of ABCA7 in brain homeostasis and Alzheimer’s disease (AD) is currently under intense scrutiny, since it has been reported that polymorphisms in the Abca7 gene and a loss of function of the protein are closely linked to excessive accumulation of amyloid peptides and disturbed cholesterol homeostasis. The blood-brain barrier (BBB), which isolates the brain from the blood compartment, is involved in both of these processes. We therefore hypothesized that ABCA7 downregulation might affect cholesterol and amyloid exchanges at the BBB. Using siRNA and primary cultures of mouse endothelial cells purified from brain microvessels and seeded on Transwell …® inserts, we investigated the role of ABCA7 in cholesterol and amyloid exchanges across the BBB. Our results showed that a decrease in ABCA7 expression at the BBB provokes in vitro a reduction in ABCA1 expression and a decrease in APOE secretion. In vitro , these decreases reduce cholesterol exchange across the BBB, particularly for high-density lipoproteins and ApoA-I particles. When ABCA7 was absent, we observed a reduction in Aβ peptide basolateral-to-apical transport in the presence of ApoA-I, with non-significant changes in the expression levels of Rage , Lrp1 , Abcb1 , Abcc1 , and Abcg2 . Our study in murine BBB model highlighted a putative new role for ABCA7 in AD via the protein’s involvement in cholesterol metabolism and amyloid clearance at the BBB. Show more

Keywords: ABCA7, Aβ peptides, Alzheimer’s disease, blood-brain barrier, cholesterol metabolism

DOI: 10.3233/JAD-170883

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1195-1211, 2018

Authors: Burgio, Francesca | Delazer, Margarete | Meneghello, Francesca | Pertl, Marie-Theres | Semenza, Carlo | Zamarian, Laura

Article Type: Research Article

Abstract: Background: Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers. Objective: To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk. Methods: In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated …Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week. Results: The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type. Conclusion: Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models. Show more

Keywords: Executive functions, intervention, medical information, neuropsychology, numerical processing

DOI: 10.3233/JAD-180461

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1213-1226, 2018

Authors: Sahoo, Aradhana | Bejanin, Alexandre | Murray, Melissa E. | Tosakulwong, Nirubol | Weigand, Stephen D. | Serie, Amanda M. | Senjem, Matthew L. | Machulda, Mary M. | Parisi, Joseph E. | Boeve, Bradley F. | Knopman, David S. | Petersen, Ronald C. | Dickson, Dennis W. | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer’s disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. Objective: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. Methods: All cases with pathologically confirmed intermediate-high probability AD from 1996–2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with …a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Results: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset (p = 0.02) and age at death (p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. Conclusion: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43. Show more

Keywords: Alzheimer’s disease, atypical AD, non-amnestic, TDP-43

DOI: 10.3233/JAD-180169

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1227-1233, 2018

Authors: Chan, Parco | Saleem, Mahwesh | Herrmann, Nathan | Mielke, Michelle M. | Haughey, Norman J. | Oh, Paul I. | Kiss, Alexander | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Biomarkers in cognitively vulnerable populations, like those with coronary artery disease (CAD), may inform earlier intervention in vascular neurodegeneration. Circulating ceramide C18:0 (CerC18:0) is associated with changes in verbal memory in early neurodegeneration and CAD progression. Objective: To investigate whether plasma CerC18:0 accumulation is associated with longitudinal declines in verbal memory performance in CAD. Methods: In addition to total CerC18:0, we assessed its relative abundance to its precursors as ratios: CerC18:0 to monohexosylceramide C18:0 (MHxCer18:0), CerC18:0 to sphingomyelin C18:0 (SM18:0), and CerC18:0 to sphingosine-1-phosphate (S1P). Verbal memory was assessed using the California Verbal Learning Test …2nd Ed. Using mixed models in 60 CAD participants, we evaluated associations between baseline CerC18:0 ratios and changes in verbal memory performance, adjusting for age, body mass index, and education. Given that cognitive decline is more rapid following onset of deficits, these associations were compared between those with possible mild vascular neurocognitive disorder (MVND). Results: Increased baseline CerC18:0 concentrations correlated with worse verbal memory performance over time (b[SE] = – 0.91[0.30], p = 0.003). Increased baseline CerC18:0/SM18:0 (b [SE] = – 1.11[`], p = 0.03) were associated with worse verbal memory performance over time. These associations were not mediated by whether or not patients had possible MVND at baseline. Conclusion: These findings support aberrant CerC18:0 metabolism as an early neurobiological change in vascular neurodegeneration. Future studies should measure enzymes responsible for conversion of sphingolipid precursors into CerC18:0 to assess enzymatic activity. Show more

Keywords: Ceramides, coronary artery disease, cognition, memory, sphingolipids

DOI: 10.3233/JAD-180030

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1235-1246, 2018

Authors: Thygesen, Camilla | Metaxas, Athanasios | Larsen, Martin R. | Finsen, Bente

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, is characterized by the intra- and extracellular aggregation and accumulation of proteins. The major molecular hallmark is the aggregation of amyloid-β (Aβ ) and hyperphosphorylated tau proteins into plaques and tangles, respectively. Evidence points to the pre-fibrillary states of protein aggregates harboring the greatest neurotoxicity. Objective: This study was designed to identify and quantify pre-fibrillary protein species enriched by their insolubility in the detergent sarkosyl in the APPSWE /PS1ΔE9 (APP/PS1) transgenic mouse model of AD. Sarkosyl insoluble fractions were isolated from the brains of APP/PS1 and …littermate wild type (Wt) mice to identify pre-fibrillary protein species associated with AD. Methods: Pre-fibrillary protein species were isolated from the brains of 3- and 24-month-old APP/PS1 and littermate Wt mice using sarkosyl extraction and subjected to quantitative proteomics analysis by the use of isobaric tags for relative and absolute quantitation (iTRAQ). Results: The sarkosyl-insoluble pre-fibrillary proteome showed differential age- and genotype-induced effects. In addition to Aβ and tau, old APP/PS1 mice showed significant enrichment in proteins in the sarkosyl fraction involved in oxidative phosphorylation and mitochondrial function. Conclusion: The results of this study implicate dysfunctional mitochondria as playing a key role of Aβ - and potentially tau-induced pathological events in the APP/PS1 transgenic mouse model of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, APPSWE/PS1ΔE9, iTRAQ, mass spectrometry, oxidative stress, proteomics, tau

DOI: 10.3233/JAD-180197

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1247-1259, 2018

Authors: Shao, Yi | Jiang, Hong | Wei, Yantao | Shi, Yingying | Shi, Ce | Wright, Clinton B. | Sun, Xiaoyan | Vanner, Elizabeth A. | Rodriguez, Anny D. | Lam, Byron L. | Rundek, Tatjana | Baumel, Barry S. | Gameiro, Giovana Rosa | Dong, Chuanhui | Wang, Jianhua

Article Type: Research Article

Abstract: Background: A detailed analysis of the tomographic thickness of intraretinal layers may provide more information on neurodegeneration in patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: The goal was to analyze tomographic thickness patterns of intraretinal layers in patients with AD andMCI. Method: Forty-nine patients (25 AD and 24 MCI) and 21 cognitively normal (CN) controls were imaged using ultra-high-resolution optical coherence tomography to obtain volumetric data centered on the fovea. The segmented intraretinal layers were retinal nerve fiber layer (RNFL), ganglion cell– inner plexiform layer (GCIPL), inner nuclear layer (INL), outer nuclear …layer (ONL), outer plexiform layer (OPL), and retinal photoreceptor (PR), in addition to the total retinal thickness(TRT). Results: The thickness differences were negative (thinning) mainly in TRT, RNFL, and GCIPL in both AD and MCI groups in comparison to CN, while the thickness differences were positive (thickening) mainly in ONL and PR in AD. GCIPL of AD and MCI was thinner in superior, nasal superior, and temporal superior quadrants, compared to CN (p < 0.05). GCIPL of the inner superior, inner nasal superior, inner temporal superior, and outer nasal superior sectors was significantly thinner in AD than CN (p < 0.05). GCIPL of the outer superior, inner temporal superior, outer nasal, and temporal superior sectors was significantly thinner in MCI than CN (p < 0.05). Conclusion: Focal thinning of the GCIPL was visualized and quantified by detailed partitions in AD and MCI, which provides specific information about neurodegeneration in MCI and AD. Show more

Keywords: Alzheimer’s disease, ETDRS partition, ganglion-inner plexiform layer, hemispheric partition, mild cognitive impairment, retinal thickness mapping, ultrahigh-resolution OCT, Zeiss elliptical partition

DOI: 10.3233/JAD-180070

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1261-1273, 2018

Authors: Sao, Tomoko | Yoshino, Yuta | Yamazaki, Kiyohiro | Ozaki, Yuki | Mori, Yoko | Ochi, Shinichiro | Yoshida, Taku | Mori, Takaaki | Iga, Jun-Ichi | Ueno, Shu-Ichi

Article Type: Research Article

Abstract: Background: Triggering receptor expressed on myeloid cells 2 (TREM2) activates the innate immune system, promotes phagocytosis by microglia, and is associated with Alzheimer’s disease (AD). The possible role of a related molecule, TREM1, in AD remains unknown. Objective: We investigated a possible role for TREM1 in AD by determining the gene expression and methylation levels of TREM1 in leukocytes from AD patients. Methods: Fifty patients with AD and 50 age-matched healthy controls were enrolled. AD patients underwent a battery of neuropsychiatric tests. Peripheral blood samples were obtained from each participant, RNA and DNA were extracted, and …samples were assessed for TREM1 mRNA expression and methylation rates at three CpG sites in the TREM1 promoter. Results: TREM1 mRNA expression levels in AD patients were significantly higher than those in controls (p = 0.008). TREM1 mRNA expression levels were not correlated with sex, age, duration of illness, APOE genotype, donepezil treatment, or scores of most neuropsychiatric tests. TREM1 mRNA expression levels in AD patients were correlated with the total score of the Montgomery-Åsberg Depression Rating Scale (p = 0.047, r = – 0.344). Methylation rates at the three CpG sites were significantly lower in AD patients than in controls. We also found a significant correlation between TREM1 mRNA expression and TREM1 DNA methylation rates (p < 0.001). Conclusion: TREM1 may be associated with the immune responses in AD, and along with hypomethylation at CpG sites in the TREM1 promoter, may become part of a biomarker panel for AD pathogenesis. Show more

Keywords: Alzheimer’s disease, cognitive function, DNA methylation, gene expression, TREM1, TREM2

DOI: 10.3233/JAD-180418

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1275-1284, 2018

Authors: Bonnechère, Bruno | Van Vooren, Mélissa | Bier, Jean-Christophe | De Breucker, Sandra | Van Hove, Olivier | Van Sint Jan, Serge | Feipel, Véronique | Jansen, Bart

Article Type: Research Article

Abstract: Background: In the past few years numerous mobile games have been developed to train the brain. There is a lack of information about the relation between the scores obtained in these games and the cognitive abilities of the patients. Objective: The aim of this study was to determine whether or not mobile games can be used to assess cognitive abilities of elderly. Methods: Twenty healthy young adults, 29 old patients with cognitive impairments (Mini-Mental State Exam (MMSE) [20– 24 ]) and 27-aged controls participated in this study. Scores obtained in 7 mobile games were correlated with …MMSE and the Addenbrooke’s Cognitive Evaluation revised (ACE-R). Results: Statistically significant differences were found for all games between patients with cognitive impairments and the aged controls. Correlations between the average scores of the games and the MMSE and ACE-R are significant (R = 0.72 [p < 0.001] and R = 0.81 [p < 0.001], respectively). Conclusion: Scores of cognitive mobile games could be used as an alternative to MMSE and ACE-R to evaluate cognitive function of aged people with and without cognitive impairment at least when MMSE is higher than 20/30. Show more

Keywords: Assessment, cognitive evaluation, dementia, mobile games, serious games

DOI: 10.3233/JAD-180224

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1285-1293, 2018

Authors: Pandareesh, Mirazkar D. | Chauhan, Ved | Chauhan, Abha

Article Type: Research Article

Abstract: Our previous study has shown beneficial effects of walnuts on memory and learning skills in transgenic mouse model of Alzheimer’s disease (AD-tg). To understand underlying mechanism, we studied here whether walnuts can reduce oxidative stress in AD. From 4 months of age, experimental AD-tg mice were fed diets containing 6% (T6) or 9% walnuts (T9) (equivalent to 1 or 1.5 oz, of walnuts per day in humans) for 5, 10, or 15 months. The control groups, i.e., AD-tg (T0) and wild-type (Wt) mice, were fed diets without walnuts. Free radicals, i.e., reactive oxygen species (ROS), lipid peroxidation, protein oxidation, and …antioxidant enzymes were assessed in these mice at different ages. AD-tg mice on control diet (T0) showed significant age-dependent increase in ROS levels, lipid peroxidation, and protein oxidation coupled with impaired activities of antioxidant enzymes [superoxide dismutase, catalase, and glutathione peroxidase] compared to Wt mice. Oxidative stress was significantly reduced in AD-tg mice on diets with walnuts (T6, T9), as evidenced by decreased levels of ROS, lipid peroxidation, and protein oxidation, as well as by enhanced activities of antioxidant enzymes compared to T0 mice. Long-term supplementation with walnuts for 10 or 15 months was more effective in reducing oxidative stress in AD-tg mice. Our findings indicate that walnuts can reduce oxidative stress, not only by scavenging free radicals, but also by protecting antioxidant status, thus leading to reduced oxidative damage to lipids and proteins in AD. Therefore, by reducing oxidative stress, a walnut-enriched diet may help reduce the risk or delay the onset and progression of AD. Show more

Keywords: Alzheimer’s disease, antioxidants, catalase, glutathione, lipid peroxidation, liver, oxidative stress, protein oxidation, reactive oxygen species, superoxide dismutase, walnuts

DOI: 10.3233/JAD-180361

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1295-1305, 2018

Authors: Abner, Erin L. | Neltner, Janna H. | Jicha, Gregory A. | Patel, Ela | Anderson, Sonya L. | Wilcock, Donna M. | Van Eldik, Linda J. | Nelson, Peter T.

Article Type: Research Article

Abstract: Data from a large autopsy series were analyzed to address questions pertinent to primary age-related tauopathy (PART) and Alzheimer’s disease (AD): what factors are associated with increased severity of neurofibrillary degeneration in brains that lack neuritic amyloid plaques?; is there an association between Apolipoprotein E (APOE ) alleles and PART pathologic severity independent of amyloid-β (Aβ ) deposits?; and, how do the stains used to detect plaques and tangles impact the experimental results? Neuropathologic data were evaluated from elderly research volunteers whose brain autopsies were performed at University of Kentucky Alzheimer’s Disease Center (UK-ADC; N = 145 subjects). …All of the included subjects’ brains lacked neuritic amyloid plaques according to the CERAD diagnostic criteria and the average final MMSE score before death was 26.8±4.6 stdev. The study incorporated evaluation of tissue with both silver histochemical stains and immunohistochemical stains to compare results; the immunohistochemical stains (Aβ and phospho-tau) were scanned and quantified using digital pathologic methods. Immunohistochemical stains provided important advantages over histochemical stains due to sensitivity and detectability via digital methods. When AD-type pathology was in its presumed earliest phases, neocortical parenchymal Aβ deposits were associated with increased medial temporal lobe neurofibrillary tangles. The observation supports the NIA-AA consensus recommendation for neuropathologic diagnoses, because even these “diffuse” Aβ deposits signal that AD pathobiologic mechanisms are occurring. Further, the data were most compatible with the hypothesis that the APOE ɛ 4 allele exerts its effect(s) via driving Aβ deposition, i.e., an “upstream” influence, rather than being associated directly with Aβ – independent PART pathology. Show more

Keywords: Aging, amyloid-β, Genie, hippocampus, MAPT, neuropathology, oldest-old, ScanScope, SNAP

DOI: 10.3233/JAD-180514

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1307-1324, 2018

Authors: Kent, Brianne A. | Strittmatter, Stephen M. | Nygaard, Haakon B.

Article Type: Research Article

Abstract: Background: Sleep disturbances have long been associated with Alzheimer’s disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. Objective: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by …EEG in AD. Methods: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. Results: Both the APP/PS1 model at 8– 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. Conclusion: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition. Show more

Keywords: Alzheimer’s disease, dementia, EEG, sleep, transgenic mice

DOI: 10.3233/JAD-180260

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1325-1336, 2018

Authors: Jones, Susan May | Killett, Anne | Mioshi, Eneida

Article Type: Research Article

Abstract: Background: Dementia Cafés are community support groups which provide post-diagnostic support for families affected by dementia. However, little is known about the characteristics of caregivers who attend Cafés. Objectives: To describe the demographic and psychosocial characteristics of caregivers who attend Dementia Cafés, and to identify which of those factors may influence the likelihood of family caregivers attending Dementia Cafés. Methods: A cross-sectional study on caregivers (n = 80; July 2016– July 2017). Resilience (Brief Resilient Coping Scale), Subjective Wellbeing (Personal Wellbeing Index), and Social Support (MOS-Social Support Survey) were measured. Café attendees and non-attendees were …compared in regards to demographic characteristics (Chi-Square tests), resilience, subjective wellbeing and social support (independent t -tests). Bivariate and multivariate regression analyses were run to detect associations between predictor variables and café attendance. Results: Caregivers who attended Cafés reported higher resilience (OR: 1.26; 95% CI 1.10–1.45; p = 0.001) and subjective wellbeing (OR: 1.63; 95% CI 1.24–2.142; p = 0.001 ); no significant difference in social support was detected. Female caregivers were more likely to attend a Café (OR: 3.23; 95% CI 1.14–9.10; p = 0.03). However, only higher subjective wellbeing (OR: 1.63; 95% CI 1.10–24.2; p = 0.02) and fewer years formal education (OR: 4.99; 95% CI 1.12–21.36; p = 0.03) predicted attendance at a café. Conclusion: Dementia Cafés may bring about benefits in resilience and subjective wellbeing, or may be best suited to those with higher resilience and wellbeing. Cafes are not being accessed by all caregiver groups. Alternative models of post-diagnostic support should be considered to increase equity of care. Show more

Keywords: Caregiver, dementia, psychosocial intervention, resilience, social support, subjective wellbeing

DOI: 10.3233/JAD-180377

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1337-1345, 2018

Authors: Lyu, Jihui | Zhang, Jingnan | Mu, Haiyan | Li, Wenjie | Champ, Mei | Xiong, Qian | Gao, Tian | Xie, Lijuan | Jin, Weiye | Yang, Wan | Cui, Mengnan | Gao, Maolong | Li, Mo

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common type of dementia, affecting millions of older people worldwide. However, pharmacological therapies have not achieved desirable clinical efficacy in the past decades. Non-pharmacological therapies have been receiving increased attention to treat dementia in recent years. Objective: This study explores the effects of music therapy on cognitive function and mental wellbeing of patients with AD. Methods: A total number of 298 AD patients with mild, moderate, or severe dementia participated in the study. The participants with each grade of severity were randomly divided into three groups, which were a …singing group, a lyric reading group, and a control group. These three groups received different interventions for three months. All participants underwent a series of tests on cognitive functions, neuropsychological symptoms, and activities of daily living at baseline, three months, and six months. Results: The analysis shows that music therapy is more effective for improving verbal fluency and for alleviating the psychiatric symptoms and caregiver distress than lyrics reading in patients with AD. Stratified analysis shows that music therapy is effective for enhancing memory and language ability in patients with mild AD and reducing the psychiatric symptoms and caregiver distress in patients with moderate or severe AD. However, no significant effect was found for activities of daily living in patients with mild, moderate, or severe AD. Conclusion: This study suggests that music therapy is effective in enhancing cognitive function and mental wellbeing and can be recommended as an alternative approach to manage AD associated symptoms. Show more

Keywords: Dementia, language, memory, music therapy

DOI: 10.3233/JAD-180183

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1347-1358, 2018

Authors: Musaeus, Christian Sandøe | Engedal, Knut | Høgh, Peter | Jelic, Vesna | Mørup, Morten | Naik, Mala | Oeksengaard, Anne-Rita | Snaedal, Jon | Wahlund, Lars-Olof | Waldemar, Gunhild | Andersen, Birgitte Bo

Article Type: Research Article

Abstract: Background: Quantitative EEG (qEEG) power could potentially be used as a diagnostic tool for Alzheimer’s disease (AD) and may further our understanding of the pathophysiology. However, the early qEEG power changes of AD are not well understood. Objective: To investigate the early changes in qEEG power and the possible correlation with memory function and cerebrospinal fluid biomarkers. In addition, whether qEEG power could discriminate between AD, mild cognitive impairment (MCI), and older healthy controls (HC) at the individual level. Methods: Standard EEGs from 138 HC, 117 MCI, and 117 AD patients were included from six Nordic …memory clinics. All EEGs were recorded consecutively before the diagnosis and were not used for the consensus diagnosis. Absolute and relative power was calculated for both eyes closed and open condition. Results: At group level using relative power, we found significant increases globally in the theta band and decreases in high frequency power in the temporal regions for eyes closed for AD and, to a lesser extent, for MCI compared to HC. Relative theta power was significantly correlated with multiple neuropsychological measures and had the largest correlation coefficient with total tau. At the individual level, the classification rate for AD and HC was 72.9% for relative power with eyes closed. Conclusion: Our findings suggest that the increase in relative theta power may be the first change in patients with dementia due to AD. At the individual level, we found a moderate classification rate for AD and HC when using EEGs alone. Show more

Keywords: Alzheimer’s disease, dementia, diagnostic, EEG, mild cognitive impairment, power

DOI: 10.3233/JAD-180300

Citation: Journal of Alzheimer's Disease, vol. 64, no. 4, pp. 1359-1371, 2018