Journal of Alzheimer's Disease - Volume 66, issue 3

Authors: Lei, Yang | Zhang, Zhi-Feng | Lei, Rui-Xue | Wang, Shu | Zhuang, Yang | Liu, An-Chun | Wu, Yan | Chen, Juan | Tang, Jun-Chun | Pan, Meng-Xian | Liu, Rui | Liao, Wei-Jing | Feng, Yu-Gong | Wan, Qi | Zheng, Mei

Article Type: Research Article

Abstract: DJ-1 (also called PARK7) is a multifunctional redox-sensitive protein that is protective against oxidative stress-induced cell death. TAR DNA-binding protein 43 (TDP-43) is a major protein component of pathological inclusions in amyotrophic lateral sclerosis and frontotemporal dementia. Reducing aberrant aggregation of TDP-43 is a potential approach to prevent cell death. To investigate whether DJ-1 might inhibit TDP-43 aggregation to exert a protective effect in oxidative stress-induced injury, we tested the protein level and subcellular localization of TDP-43 and DJ-1 in SH-SY5Y cells transfected with wild-type DJ-1, DJ-1 mutant (L166P) cDNA, or DJ-1 siRNA. We show that oxidative stress induced by …paraquat leads to the formation of cytosolic TDP-43 aggregation in SH-SY5Y cells. DJ-1 overexpression decreases paraquat-induced cytoplasmic accumulation of TDP-43 in SH-SY5Y cells and protects against paraquat-induced cell death. Transfection of DJ-1 L166P mutant or DJ-1 siRNA leads to increased cytosolic aggregation of TDP-43 in paraquat-treated SH-SY5Y cells and promotes cell death. These data suggest that DJ-1 may protect against oxidative stress-induced cell death through the suppression of cytoplasmic TDP-43 aggregation. Show more

Keywords: Amyotrophic lateral sclerosis, oxidative stress, PARK7, TAR DNA-binding protein 43

DOI: 10.3233/JAD-180460

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1001-1014, 2018

Authors: Owens, Tyler E. | Machulda, Mary M. | Duffy, Joseph R. | Strand, Edythe A. | Clark, Heather M. | Boland, Sarah | Martin, Peter R. | Lowe, Val J. | Jack Jr, Clifford R | Whitwell, Jennifer L. | Josephs, Keith A.

Article Type: Research Article

Abstract: Background: Neuropsychological assessment can add essential information to the characterization of individuals presenting with the logopenic variant of primary progressive aphasia (lvPPA). Objective: This study examined the neuropsychological characteristics of lvPPA patients. We also examined differences in regional and whole brain atrophy based on neuropsychological profiles. Methods: We conducted a hierarchical cluster analysis on memory, executive functioning, and visuospatial neuropsychological test data for 56 individuals with lvPPA. We then compared resultant clusters to left middle temporal, inferior parietal, and superior parietal regions-of-interest using multivariate analysis of covariance. We also performed voxel-level analyses. Results: We …identified three clusters characterized as lvPPA with no neurocognitive impairment (n  = 5), lvPPA with mild neurocognitive deficits (n  = 23), and lvPPA with marked cognitive deficits (n  = 28). WAB-AQ was associated with left middle temporal volume. Superior parietal volumes were smaller for the lvPPA group with marked cognitive symptoms compared to the less severe groups. Voxel-level analyses showed greater atrophy in temporal, parietal, lateral occipital, and frontal regions, left worse than right. Age, disease duration, gender, WAB-AQ, and PiB-PET did not account for differences between groups. Conclusions: LvPPA patients without cognitive deficits in other domains were relatively uncommon while 50% of our sample exhibited pronounced neurocognitive deficits outside the language domain. Pronounced cognitive deficits in lvPPA are associated with widespread atrophy, left worse than right. Our study underscores the importance of examining neuropsychological function in addition to language in patients with lvPPA. Show more

Keywords: Logopenic aphasia, neuropsychological assessment, primary progressive aphasia, volumetric MRI, voxel-wise analyses

DOI: 10.3233/JAD-171175

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1015-1025, 2018

Authors: Handels, Ron L.H. | Sköldunger, Anders | Bieber, Anja | Edwards, Rhiannon Tudor | Gonçalves-Pereira, Manuel | Hopper, Louise | Irving, Kate | Jelley, Hannah | Kerpershoek, Liselot | Marques, Maria J. | Meyer, Gabriele | Michelet, Mona | Portolani, Elisa | Røsvik, Janne | Selbaek, Geir | Stephan, Astrid | de Vugt, Marjolein | Wolfs, Claire | Woods, Bob | Zanetti, Orazio | Verhey, Frans | Wimo, Anders | and Actifcare consortium

Article Type: Research Article

Abstract: Background: With 10.5 million people with dementia in Europe and $301 billion associated costs, governments face challenges organizing access to care. Objective: To examine the costs related to formal and informal care use and quality of life for people with dementia in eight European countries, and explore the association with unmet needs. Methods: Cross-sectional data from 451 persons with dementia and their informal caregivers of the Actifcare cohort study were obtained. Formal and informal care use was multiplied by country specific unit prices of services. Needs were measured using the CANE and health-related quality of life …(HRQOL) of the person with dementia (both self- and proxy-rated) and informal caregiver’s quality of life using EQ-5D-5L, ICECAP-O, DEMQOL-U, and CarerQol utility scores. The association between costs and country, European region, and unmet needs was assessed using multi-level linear regression. Results: Self-rated EQ-5D-5L utility score was higher than proxy-rated (0.84 and 0.71, respectively). Informal caregivers’ utility score was 0.84. Across eight countries annual mean costs of formal and informal care were approximately € 17,000. Unmet needs were not associated with annual costs of care, nor with proxy-rated HRQOL, but were associated with self-rated HRQOL. Conclusion: We found varying relationships between unmet needs and quality of life, and no association between unmet needs and care costs, although the results were sensitive to various factors. Future research should further investigate the relation between unmet needs, quality of life and costs to generate a better understanding of the effects of (un)timely access to care. Show more

Keywords: Access to care, costs, dementia, health-economics, quality of life, unmet needs

DOI: 10.3233/JAD-180275

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1027-1040, 2018

Authors: Walker, Keenan A. | Windham, B. Gwen | Brown IV, Charles H. | Knopman, David S. | Jack Jr, Clifford R. | Mosley Jr, Thomas H. | Selvin, Elizabeth | Wong, Dean F. | Hughes, Timothy M. | Zhou, Yun | Gross, Alden L. | Gottesman, Rebecca F.

Article Type: Research Article

Abstract: Background: Although inflammation has been implicated in the pathogenesis of Alzheimer’s disease, the effects of systemic inflammation on brain amyloid deposition remain unclear. Objective: We examined the association of midlife and late-life systemic inflammation with late-life brain amyloid levels in a community sample of non-demented older adults from the Atherosclerosis Risk in Communities (ARIC) – PET Study. Methods: 339 non-demented participants (age: 75 [SD 5]) were recruited from the ARIC Study to undergo florbetapir PET (amyloid) imaging. Blood levels of high sensitivity C-reactive protein (CRP), a marker of systemic inflammation, were measured 22 years (Visit 2), …16 years (Visit 4), and up to 2 years before PET imaging (Visit 5). Elevated brain amyloid deposition (standardized uptake value ratio >1.2) was the primary outcome. Results: Our primary analyses found no association of midlife and late-life CRP with late-life brain amyloid levels. However, in secondary stratified analyses, we found that higher midlife (Visit 2) CRP was associated with elevated amyloid among males (OR 1.65, 95% CI: 1.13–2.42), and among white (OR 1.33, 95% CI: 1.02–1.75), but not African American, participants (p -interactions<0.05). Among male participants, those who maintained high CRP levels (≥3 mg/L) throughout mid- and late-life were most likely to have elevated brain amyloid (OR, 8.81; 95% CI: 1.23, 62.91). Conclusions: Although our primary analysis does not support an association between systemic inflammation and brain amyloid deposition, we found evidence for sex- and race-dependent associations. However, findings from subgroup analyses should be interpreted with caution. Show more

Keywords: Alzheimer’s disease, amyloid-beta, C-reactive protein, florbetapir PET, immune system, inflammation

DOI: 10.3233/JAD-180469

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1041-1052, 2018

Authors: Rahman, M. Mahafuzur | Westermark, Gunilla T. | Zetterberg, Henrik | Härd, Torleif | Sandgren, Mats

Article Type: Research Article

Abstract: Aggregation and deposition of misfolded amyloid-β (Aβ) peptide in the brain is central to Alzheimer’s disease (AD). Oligomeric, protofibrillar, and fibrillar forms of Aβ are believed to be neurotoxic and cause neurodegeneration in AD, but the toxicity mechanisms are not well understood and may involve Aβ-interacting molecular partners. In a previous study, we identified potential Aβ42 protofibrillar-binding proteins in serum and cerebrospinal fluid (CSF) using an engineered version of Aβ42 (Aβ42 CC) that forms protofibrils, but not fibrils. Here we studied binding of proteins to Aβ42 fibrils in AD and non-AD CSF and compared these with protofibrillar …Aβ42 CC-binding partners. Aβ42 fibrils sequestered 2.4-fold more proteins than Aβ42 CC protofibrils. Proteins with selective binding to fibrillar aggregates with low nanomolar affinity were identified. We also found that protofibrillar and fibrillar Aβ-binding proteins represent distinct functional categories. Aβ42 CC protofibrils triggered interactions with proteins involved in catalytic activities, like transferases and oxidoreductases, while Aβ42 fibrils were more likely involved in binding to proteoglycans, growth factors and neuron-associated proteins, e.g., neurexin-1, -2, and -3. Interestingly, 10 brain-enriched proteins were identified among the fibril-binding proteins, while protofibril-extracted proteins had more general expression patterns. Both types of Aβ aggregates bound several extracellular proteins. Additionally, we list a set of CSF proteins that might have potential to discriminate between AD and non-AD CSF samples. The results may be of relevance both for biomarker studies and for studies of Aβ-related toxicity mechanisms. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomolecular interaction, cerebrospinal fluid, fibrils, protofibrils

DOI: 10.3233/JAD-180596

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1053-1064, 2018

Authors: Mohammad, Dana | Ellis, Courtney | Rau, Allison | Rosenberg, Paul B. | Mintzer, Jacobo | Ruthirakuhan, Myuri | Herrmann, Nathan | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Apathy is a prevalent and problematic neuropsychiatric symptom in those with dementia that is emerging as a treatment target, necessitating accurate assessment. While many apathy scales are available, not all have been developed for use exclusively in dementia, and psychometric properties may vary across different populations. This systematic review aimed to provide an overview of the psychometric properties of apathy scales used in Alzheimer’s disease (AD) and related dementias, as well as rate the methodological quality of supporting studies. In addition, for those scales identified, performance in clinical trials was reviewed. A search was conducted through Medline, Psychinfo, Embase, Cochrane …Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. Articles that reported psychometric properties of an apathy scale in an AD or mixed dementia population were included. Of 15 articles, the methodological quality ratings of the studies ranged from adequate to excellent. Three clinical trials and two pooled analyses of clinical trials were included that used apathy scales evaluated in this review. Three scales emerged. The Neuropsychiatric Inventory apathy subscale (NPI-apathy) and the Apathy Evaluation Scale (AES) had the greatest number of studies evaluating psychometric properties and were also used in the clinical trials and have shown sensitivity to change. The Dementia Apathy Interview and Rating demonstrated excellent values of internal consistency, validity, and reliability for use in an AD population. Future research should address comparative scale performance and assess ability to distinguish subtypes of apathy. Validation may include evaluation of performance against specific imaging defined deficits. Show more

Keywords: Alzheimer’s disease, apathy, dementia, diagnosis, psychometrics

DOI: 10.3233/JAD-180485

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1065-1082, 2018

Authors: Lucchelli, Federica | Saetti, Maria Cristina | Spinnler, Hans

Article Type: Research Article

Abstract: A still unsettled issue of amnesia concerns the differential contributions to recall impairment of the underlying retrieval and storage abilities. The aim of the present study was to disentangle and to measure such roles in the recall of past public events comparing patients with degenerative amnesia and healthy elderly. The experiment included 44 healthy elderly and two groups of participants with degenerative amnesia, namely 17 patients with amnestic mild cognitive impairment and 22 mild Alzheimer’s disease patients. Recall of famous past public events was assessed by means of a 52-item questionnaire standardized for the Italian population. A latent-variable approach was …adopted in order to infer the contributions of retrieval and storage to the recall performances. A stochastic model was adopted, which in a previous study of recall of recent and remote past public events in healthy elderly succeeded to prove reduced retrieval efficiency for more recent events. The results of the present study suggest that retrieval is more fragile than storage in all three experimental groups. A storage impairment turned out only in the Alzheimer’s disease group, where it was limited to more recent memories. In view of the combined roles of the hippocampus and cortex in past memory processing, our results are consistent with the hypothesis that the degenerative process primarily impairs the strategic memory search. However, the sufficiency criterion of the adopted Markov model fell short of significance. Due to this statistical shortcoming, our conclusions, though consistent with the clinical predictions, are to be taken as provisional. Show more

Keywords: Alzheimer’s disease, latent variables, Markov chains, mild cognitive impairment, past public events, retrograde memory

DOI: 10.3233/JAD-180436

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1083-1094, 2018

Authors: Al-Janabi, Omar M. | Brown, Christopher A. | Bahrani, Ahmed A. | Abner, Erin L. | Barber, Justin M. | Gold, Brian T. | Goldstein, Larry B. | Murphy, Ronan R. | Nelson, Peter T. | Johnson, Nathan F. | Shaw, Leslie M. | Smith, Charles D. | Trojanowski, John Q. | Wilcock, Donna M. | Jicha, Gregory A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology and hypertension (HTN) are risk factors for development of white matter (WM) alterations and might be independently associated with these alterations in older adults. Objective: To evaluate the independent and synergistic effects of HTN and AD pathology on WM alterations. Methods: Clinical measures of cerebrovascular disease risk were collected from 62 participants in University of Kentucky Alzheimer’s Disease Center studies who also had cerebrospinal fluid (CSF) sampling and MRI brain scans. CSF Aβ1-42 levels were measured as a marker of AD, and fluid-attenuated inversion recovery imaging and diffusion tensor imaging …were obtained to assess WM macro- and microstructural properties. Linear regression analyses were used to assess the relationships among WM alterations, cerebrovascular disease risk, and AD pathology. Voxelwise analyses were performed to examine spatial patterns of WM alteration associated with each pathology. Results: HTN and CSF Aβ1-42 levels were each associated with white matter hyperintensities (WMH). Also, CSF Aβ1-42 levels were associated with alterations in normal appearing white matter fractional anisotropy (NAWM-FA), whereas HTN was marginally associated with alterations in NAWM-FA. Linear regression analyses demonstrated significant main effects of HTN and CSF Aβ1-42 on WMH volume, but no significant HTN×CSF Aβ1-42 interaction. Furthermore, voxelwise analyses showed unique patterns of WM alteration associated with hypertension and CSF Aβ1-42 . Conclusion: Associations of HTN and lower CSF Aβ1-42 with WM alteration were statistically and spatially distinct, suggesting independent rather than synergistic effects. Considering such spatial distributions may improve diagnostic accuracy to address each underlying pathology. Show more

Keywords: Alzheimer’s disease, Aβ1-42 , hypertension, white matter alteration

DOI: 10.3233/JAD-180663

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1095-1104, 2018

Authors: Florek, Lisa | Tiepolt, Solveig | Schroeter, Matthias L. | Berrouschot, Jörg | Saur, Dorothee | Hesse, Swen | Jochimsen, Thies | Luthardt, Julia | Sattler, Bernhard | Patt, Marianne | Hoffmann, Karl-Titus | Villringer, Arno | Classen, Joseph | Gertz, Hermann-Josef | Sabri, Osama | Barthel, Henryk

Article Type: Research Article

Abstract: Background: Current research diagnostic criteria for Alzheimer’s disease (AD) and mild cognitive impairment (MCI) due to AD include biomarkers to supplement clinical testing. Recently, we demonstrated that dual time-point [18 F]FBB PET is able to deliver both blood flow and amyloid-β (Aβ) load surrogates. Objective: The aim of this study was to investigate whether these surrogates can be utilized as AD biomarkers. Methods: 112 subjects (41 with MCI, 50 with probable/possible AD, 21 with other dementias) underwent dual time-point [18 F]FBB PET. Data were visually and relative quantitatively (Herholz scores for the early and composite SUVRs …for the late PET data) analyzed. Results: In the early images AD-typical patterns were present in 42% /27% /33% of probable/possible AD/MCI/other dementia cases. In late [18 F]FBB PET, 42% /29% /38% of probable/possible AD/ MCI/other dementia cases were Aβ-positive. 17% of the MCIs were categorized as “MCI due to AD-high likelihood”, 44% of the probable ADs as “probable AD with high evidence of AD pathophysiological process” and 28% of the possible ADs as “possible AD with evidence of AD pathophysiological process”. 27% of all subjects showed a positive diagnostic and progression biomarker. Herholz scores were lower (0.85±0.05 versus 0.88±0.04, p  = 0.015) for probable/possible AD versus MCI. Composite late phase SUVRs were significantly higher (1.65±0.23 versus 1.15±0.17, p  < 0.005) in Aβ-positive versus Aβ-negative patients. Herholz and MMSE scores were positively correlated (R = 0.30 p  = 0.006). Conclusion: Dual time-point [18 F]FBB PET provides dual biomarker information which enables to categorize MCI and AD dementia patients according to established diagnostic criteria. Thus, dual time-point [18 F]FBB PET has great potential to supplement diagnostic dementia workups. Show more

Keywords: Alzheimer’s disease, dual biomarker, dual-phase, dual time-point, florbetaben, mild cognitive impairment

DOI: 10.3233/JAD-180522

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1105-1116, 2018

Authors: Kempuraj, Duraisamy | Selvakumar, Govindhasamy Pushpavathi | Thangavel, Ramasamy | Ahmed, Mohammad Ejaz | Zaheer, Smita | Kumar, Keerthana Kuppamma | Yelam, Anudeep | Kaur, Harleen | Dubova, Iuliia | Raikwar, Sudhanshu P. | Iyer, Shankar S. | Zaheer, Asgar

Article Type: Research Article

Abstract: Parkinson’s disease (PD) is characterized by the presence of inflammation-mediated dopaminergic neurodegeneration in the substantia nigra. Inflammatory mediators from activated microglia, astrocytes, neurons, T-cells and mast cells mediate neuroinflammation and neurodegeneration. Administration of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induces PD like motor deficits in rodents. 1-methyl-4-phenylpyridinium (MPP+ ), a toxic metabolite of MPTP activates glial cells, neurons and mast cells to release neuroinflammatory mediators. Glia maturation factor (GMF), mast cells and proteinase activated receptor-2 (PAR-2) are implicated in neuroinflammation. Alpha-synuclein which induces neurodegeneration increases PAR-2 expression in the brain. However, the exact mechanisms are not yet understood. In this study, we quantified inflammatory …mediators in the brains of MPTP-administered wild type (Wt), GMF-knockout (GMF-KO), and mast cell knockout (MC-KO) mice. Additionally, we analyzed the effect of MPP+ , GMF, and mast cell proteases on PAR-2 expression in astrocytes and neurons in vitro . Results show that the levels of interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α ), and the chemokine (C-C motif) ligand 2 (CCL2) were lesser in the brains of GMF-KO mice and MC-KO mice when compared to Wt mice brain after MPTP administration. Incubation of astrocytes and neurons with MPP+ , GMF, and mouse mast cell protease-6 (MMCP-6) and MMCP-7 increased the expression of PAR-2. Our studies show that the absence of mast cells and GMF reduce the expression of neuroinflammatory mediators in the brain. We conclude that GMF along with mast cell interactions with glial cells and neurons during neuroinflammation can be explored as a new therapeutic target for PD and other neuroinflammatory disorders. Show more

Keywords: Astrocytes, cytokines, glia maturation factor, mast cells, mouse mast cell proteases, Parkinson’s disease, PAR-2

DOI: 10.3233/JAD-180786

Citation: Journal of Alzheimer's Disease, vol. 66, no. 3, pp. 1117-1129, 2018