Journal of Alzheimer's Disease - Volume 61, issue 2

Authors: Kimura, Akio | Yoshikura, Nobuaki | Hayashi, Yuichi | Inuzuka, Takashi

Article Type: Research Article

Abstract: Background: Chronic neuroinflammation has been implicated in Alzheimer’s disease (AD) pathology. Objective: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients. Methods: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets …the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB). Results: CSF CCL2 levels correlated significantly with the severity (p  = 0.023) and the extent (p  = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p  = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p  = 0.020), the extent of VOI atrophy (p  = 0.015), and the ratio of VOI/GM atrophy (r  = –0.358, p  = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p  = 0.0497) and FAB scores (p  = 0.016). Conclusions: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD. Show more

Keywords: Amyloid-β, anti-Aβ autoantibody, chemokine CCL2, cytokine, medial temporal lobe atrophy, voxel-based morphometry

DOI: 10.3233/JAD-170519

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 581-588, 2018

Authors: Slachevsky, Andrea | Barraza, Paulo | Hornberger, Michael | Muñoz-Neira, Carlos | Flanagan, Emma | Henríquez, Fernando | Bravo, Eduardo | Farías, Mauricio | Delgado, Carolina

Article Type: Research Article

Abstract: Episodic memory tests with cued recall, such as the Free and Cued Selective Reminding Test (FCSRT), allow for the delineation of hippocampal and prefrontal atrophy contributions to memory performance in Alzheimer’s disease (AD). Both Word and Picture versions of the test exist but show different profiles, with the Picture version usually scoring higher across different cohorts. One possible explanation for this divergent performance between the different modality versions of the test might be that they rely on different sets of neural correlates. The current study explores this by contrasting the neural correlates of the Word and Picture versions of the …FCSRT with voxel-based morphometry (VBM) in AD and healthy subjects. We predicted that the Picture version would be associated with different cortical regions than the Word version, which might be more hippocampal-centric. When comparing 35 AD patients and 34 controls, AD patients exhibited impairments on both versions of the FCSRT and both groups performed higher in the Picture version. A region of interest analysis based on prior work revealed significant correlations between free recall of either version with atrophy of the temporal pole and hippocampal regions. Thus, contrary to expectations, performance on both the Word and the Picture version of the FCSRT is associated with largely overlapping networks. Free recall is associated with hippocampal volume and might be properly considered as an indicator of hippocampal structural integrity. Show more

Keywords: Alzheimer’s disease, biomarkers, episodic memory, FCSRT Picture version, FCSRT Word version, Free and Cued Selective Reminding Test, hippocampus, voxel based morphometry

DOI: 10.3233/JAD-160973

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 589-600, 2018

Authors: Dougherty, Ryan J. | Lindheimer, Jacob B. | Stegner, Aaron J. | Van Riper, Stephanie | Okonkwo, Ozioma C. | Cook, Dane B.

Article Type: Research Article

Abstract: Cardiorespiratory fitness (CRF) is routinely investigated in older adults; however, the most appropriate CRF measure to use for this population has received inadequate attention. This study aimed to 1) evaluate the reliability and validity of the oxygen uptake efficiency slope (OUES) as a sub-maximal measurement of CRF; 2) examine demographic, risk-factor, and exercise testing differences in older adults who satisfied standardized criteria for a peak oxygen consumption (V ̇ O2peak ) test compared to those who did not; and 3) determine the difference between directly measured V ̇ O2peak values and OUES-predicted V …̇ O2peak values. One hundred ten enrollees from the Wisconsin Registry for Alzheimer’s Prevention participated in this study. Participants performed a graded maximal exercise test and wore an accelerometer for 7 days. For each participant, the OUES was calculated at 75%, 90%, and 100% of exercise duration. V ̇ O2peak was recorded at peak effort, and one week of physical activity behavior was measured. OUES values calculated at separate relative exercise durations displayed excellent reliability (ICC = 0.995; p  < 0.001), and were strongly correlated with V ̇ O2peak (r range  = 0.801–0.909; p  < 0.001). As hypothesized, participants who did not satisfy V ̇ O2peak criteria were significantly older than those who satisfied criteria (p  = 0.049) and attained a directly measured V ̇ O2peak that was 2.31 mL·kg·min-1 less than the value that was predicted by OUES V ̇ O2peak (p  = 0.003). Older adults are less likely to satisfy V ̇ O2peak criteria, which results in an underestimation of their CRF. Without adhering to standardized criteria, V ̇ O2peak measurement error may lead to misinterpretation of CRF and age-related associations. Here, we conclude that OUES is a reliable, valid measurement of CRF which does not require achievement of standardized criteria. Show more

Keywords: Alzheimer’s disease, cardiopulmonary exercise testing, maximal exercise test, oxygen consumption, oxygen uptake efficiency slope, sub-maximal exercise test

DOI: 10.3233/JAD-170576

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 601-611, 2018

Authors: Wu, Liyong | Liu, Jia | Feng, Xueyan | Dong, Jing | Qin, Wei | Liu, Yang | Wang, Jingjuan | Lu, Jie | Chen, Kewei | Wang, Yuping | Jia, Jianping

Article Type: Research Article

Abstract: Frontotemporal dementia with parkinsonism-linked to chromosome 17 (FTDP-17) is a rare autosomal dominant neurodegenerative disorder. Most patients with FTDP-17 carry the mutation in the microtubule-associated protein tau (MAPT) gene. Striatum is predominantly and early affected in FTDP-17. Five family members (two symptomatic patients and three presymptomatic mutation carriers) from a Chinese pedigree of FTDP-17 with N279K mutation in MAPT were enrolled. Parkinsonism was the initial symptom for symptomatic patients. 2b-carbomethoxy-3b-(4-trimethylstannylphenyl) tropane (11 C-CFT) uptake was obviously affected in the putamen of two presymptomatic mutation carriers. Presymptomatic case 3, whose 11 C-CFT uptake in the right putamen was normal at baseline, …was still free of parkinsonism during follow-up. In conclusion, 11 C-CFT-positron emission tomography could be a potential biomarker for the presymptomatic stage of FTDP-17 to predict the disease onset. Show more

Keywords: 11C-CFT-PET, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), microtubule-associated protein tau (MAPT), presymptomatic mutation carriers

DOI: 10.3233/JAD-170561

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 613-618, 2018

Authors: Saksida, Tamara | Koprivica, Ivan | Vujičić, Milica | Stošić-Grujičić, Stanislava | Perović, Milka | Kanazir, Selma | Stojanović, Ivana

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by accumulation of amyloid-β plaques that further promotes microglia-mediated neuroinflammatory responses and inflammation in the brain. Emerging data are revealing the relation between gut-associated lymphoid tissue (GALT) cells and CNS, as effector cells primed in the gut might home to the brain. This study aimed to determine cell composition of GALT in 5xFAD mice, an established model for AD. Immune cells isolated from Peyer’s patches (PP) and mesenteric lymph nodes (MLN) were stained with surface and intracellular markers for T helper (Th) subpopulations, B lymphocytes and macrophages and analyzed cytofluorimetrically, while cytokine expression and production …were determined by qPCR and ELISA, respectively. Inflammation was detected in GALT of 5xFAD mice with established AD pathology. Although the production of IFN-γ, IL-4, and IL-10 was comparable between the strains, lower IL-17 production was observed in PP and MLN cells. This phenomenon could not be attributed to a lower abundance of Th17 cells, or cytokines that initiate their formation or propagation (TGF-β, IL-6, and IL-23). Also, reduced IL-17 production was not a consequence of altered Il-17 mRNA transcription or deficiency of Rorγt, a key transcription factor for IL-17. However, the expression of miR-155 (a non-coding micro RNA that promotes the development of Th17 cells), was significantly lower in MLN cells of 5xFAD mice. In contrast, mice without AD neuropathology did not have inflammation in GALT or altered Th17 numbers, nor decreased IL-17 production. In conclusion, the observed changes in GALT of 5xFAD mice mirror the disease progression and might reflect inadequate immune surveillance in the gut and lead to enhanced AD pathology. Show more

Keywords: 5xFAD mice, amyloid-β, IL-17, mesenteric lymph nodes, Peyer’s patches

DOI: 10.3233/JAD-170538

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 619-630, 2018

Authors: Lao, Patrick J. | Handen, Ben L. | Betthauser, Tobey J. | Mihaila, Iulia | Hartley, Sigan L. | Cohen, Annie D. | Tudorascu, Dana L. | Bulova, Peter D. | Lopresti, Brian J. | Tumuluru, Rameshwari V. | Murali, Dhanabalan | Mathis, Chester A. | Barnhart, Todd E. | Stone, Charles K. | Price, Julie C. | Devenny, Darlynne A. | Johnson, Sterling C. | Klunk, William E. | Christian, Bradley T.

Article Type: Research Article

Abstract: Background: The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer’s disease (AD). Objective: The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods: Twenty-four adults (13 male, 11 female; 39±7 years) with DS underwent [11 C]PiB, [18 F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results: Positive associations …of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions: In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions. Show more

Keywords: Alzheimer’s disease, amyloid-β, Down syndrome, fluorodeoxyglucose, glucose metabolism, gray matter, magnetic resonance imaging, Pittsburgh compound B

DOI: 10.3233/JAD-170720

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 631-644, 2018

Authors: Chen, Dong-Wan | Wang, Jun | Zhang, Li-Li | Wang, Yan-Jiang | Gao, Chang-Yue

Article Type: Research Article

Abstract: Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer’s disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. …However, no significant difference was found in Aβ40 , total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, sleep disorder, tau

DOI: 10.3233/JAD-170032

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 645-651, 2018

Authors: Flanagan, Margaret E. | Larson, Eric B. | Walker, Rod L. | Keene, C. Dirk | Postupna, Nadia | Cholerton, Brenna | Sonnen, Joshua A. | Dublin, Sascha | Crane, Paul K. | Montine, Thomas J.

Article Type: Research Article

Abstract: Analgesics are commonly used by older adults, raising the question of whether their use might contribute to dementia risk and neuropathologic changes of Alzheimer’s disease (AD). The Adult Changes in Thought (ACT) study is a population-based study of brain aging and incident dementia among people 65 years or older who are community dwelling and not demented at entry. Amyloid-β (Aβ)42 and phospho-tau were quantified using Histelide in regions of cerebral cortex from 420 brain autopsies. Total standard daily doses of prescription opioid and non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure during a defined 10-year exposure window were identified using automated …pharmacy dispensing data and used to classify people as having no/low, intermediate, or high exposure. People with high NSAID exposure had significantly greater Aβ42 concentration in middle frontal gyrus and superior and middle temporal gyri, but not inferior parietal lobule; no Aβ42 regional concentration was associated with prescription opioid usage. People with high opioid usage had significantly greater concentration of phospho-tau in middle frontal gyrus than people with little-to-no opioid usage. Consistent with our previous studies, findings suggest that high levels of NSAID use in older individuals may promote Aβ42 accumulation in cerebral cortex. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuropathology, non-steroidal anti-inflammatory drugs, opioids

DOI: 10.3233/JAD-170414

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 653-662, 2018

Authors: El Haj, Mohamad | Coello, Yann | Kapogiannis, Dimitrios | Gallouj, Karim | Antoine, Pascal

Article Type: Research Article

Abstract: Relatively to “standard” prospective memory, i.e., remembering to perform a future action, little is known about negative prospective memory, i.e., remembering not to perform a future action. This study investigated the latter ability in Alzheimer’s disease (AD). AD participants and healthy older adults were asked to click on the keyboard or not to click on it when a cue word was encountered. Results showed more omissions (i.e., forgetting to click the keyboard when the instruction was to do so) in AD participants than in healthy older adults, suggesting a prospective memory deficit. Interestingly, more commissions (i.e., clicking the keyboard when …the instruction was not to do so) were also observed in AD participants than in healthy older adults. Similar levels of commissions and omissions were observed in AD participants and in healthy older adults. Also, commissions and omissions were correlated with performance on an inhibition assessment task. Our findings reveal that AD is characterized by not only difficulty in the retrieval of recent information, but also difficulty to inhibit no-longer appropriate stimulus-response associations previously learned, suggesting a specific deficit of negative prospective memory in AD. Show more

Keywords: Alzheimer’s disease, commission, inhibition, negative prospective memory, prospective memory

DOI: 10.3233/JAD-170807

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 663-672, 2018

Authors: Law, Bernard M. | Guest, Amy L. | Pullen, Matthew W. J. | Perkinton, Michael S. | Williams, Robert J.

Article Type: Research Article

Abstract: Sequential cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (β-secretase) followed by theγ-secretase complex, is strongly implicated in Alzheimer’s disease (AD) but the initial cellular responses to these cleavage events are not fully defined. β-secretase-mediated AβPP processing yields an extracellular domain (sAβPPβ) and a C-terminal fragment of AβPP of 99 amino acids (C99). Subsequent cleavage by γ-secretase produces amyloid-β (Aβ) and an AβPP intracellular domain (AICD). A cellular screen based on the generation of AICD from an AβPP-Gal4 fusion protein was adapted by introducing familial AD (FAD) mutations into the AβPP sequence and linking the assay to Gal4-UAS driven …luciferase and GFP expression, to identify responses immediately downstream of AβPP processing in neurons with a focus on the transcription factor Foxo3a which has been implicated in neurodegeneration. The K670N/M671L, E682K, E693G, and V717I FAD mutations and the A673T protective mutation, were introduced into the AβPP sequence by site directed mutagenesis. When expressed in mouse cortical neurons, AβPP-Gal4-UAS driven luciferase and GFP expression was substantially reduced by γ-secretase inhibitors, lowered by β-secretase inhibitors, and enhanced by α -secretase inhibitors suggesting that AICD is a product of the βγ-secretase pathway. AβPP-Gal4-UAS driven GFP expression was exploited to identify individual neurons undergoing amyloidogenic AβPP processing, revealing increased nuclear localization of Foxo3a and enhanced Foxo3a-mediated transcription downstream of AICD production. Foxo3a translocation was not driven by AICD directly but correlated with reduced Akt phosphorylation. Collectively this suggests that βγ-secretase-mediated AβPP processing couples to Foxo3a which could be an early neuronal signaling response in AD. Show more

Keywords: AICD, Akt, Alzheimer’s disease, amyloid-β protein precursor, apoptosis, β-secretase, Forkhead transcription factor, FOXO3 protein, γ-secretase, neurodegeneration

DOI: 10.3233/JAD-170393

Citation: Journal of Alzheimer's Disease, vol. 61, no. 2, pp. 673-688, 2018