Journal of Alzheimer's Disease - Volume 61, issue 1

Authors: Manzine, Patricia R. | Pelucchi, Silvia | Horst, Maria A. | Vale, Francisco A.C. | Pavarini, Sofia C.I. | Audano, Matteo | Mitro, Nico | Di Luca, Monica | Marcello, Elena | Cominetti, Márcia R.

Article Type: Research Article

Abstract: ADAM10 is the α-secretase that cleaves amyloid-β protein precursor in the non-amyloidogenic pathway in Alzheimer’s disease (AD) and is known to be regulated by different microRNAs (miRNAs), which are post-transcriptional regulators related to several biological and pathological processes, including AD. Here we proposed to explore and validate miRNAs that have direct or indirect relations to the AD pathophysiology and ADAM10 gene. Approximately 700 miRNAs were analyzed and 21 differentially expressed miRNAs were validated in a sample of 21 AD subjects and 17 cognitively healthy matched controls. SH-SY5Y cells were transfected with miR-144-5p, miR-221, and miR-374 mimics and inhibitors, and ADAM10 …protein levels were evaluated. miR-144-5p, miR-221, and miR-374 were downregulated in AD. The overexpression of miR-221 in SH-SY5Y cells resulted in ADAM10 reduction and its inhibition in ADAM10 increased. These findings show that miR-221 can be a new potential therapeutic target for increasing ADAM10 levels in AD. In addition, these results can contribute to the better understanding of ADAM10 post-transcriptional regulation. Show more

Keywords: ADAM10 protein, aging, Alzheimer’s disease, biomarkers, microRNAs

DOI: 10.3233/JAD-170592

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 113-123, 2018

Authors: Bagheri, Nasser | Wangdi, Kinley | Cherbuin, Nicolas | Anstey, Kaarin J.

Article Type: Research Article

Abstract: We have a poor understanding of whether dementia clusters geographically, how this occurs, and how dementia may relate to socio-demographic factors. To shed light on these important questions, this study aimed to compute a dementia risk score for individuals to assess spatial variation of dementia risk, identify significant clusters (hotspots), and explore their association with socioeconomic status. We used clinical records from 16 general practices (468 Statistical Area level 1 s, N  = 14,746) from the city of west Adelaide, Australia for the duration of 1 January 2012 to 31 December 2014. Dementia risk was estimated using The Australian National University-Alzheimer’s Disease …Risk Index. Hotspot analyses were applied to examine potential clusters in dementia risk at small area level. Significant hotspots were observed in eastern and southern areas while coldspots were observed in the western area within the study perimeter. Additionally, significant hotspots were observed in low socio-economic communities. We found dementia risk scores increased with age, sex (female), high cholesterol, no physical activity, living alone (widow, divorced, separated, or never married), and co-morbidities such as diabetes and depression. Similarly, smoking was associated with a lower dementia risk score. The identification of dementia risk clusters may provide insight into possible geographical variations in risk factors for dementia and quantify these risks at the community level. As such, this research may enable policy makers to tailor early prevention strategies to the correct individuals within their precise locations. Show more

Keywords: Dementia, dementia risk score tools, general practice data, geospatial analysis, hotspots, spatial variation

DOI: 10.3233/JAD-170079

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 125-134, 2018

Authors: Álvarez, Ignacio | Aguilar, Miquel | González, Jose Manuel | Ysamat, Montse | Lorenzo-Bosquet, Carles | Alonso, Alvaro | Tartari, Juan Pablo | Romero, Silvia | Diez-Fairen, Monica | Carcel, Maria | Pujalte, Francisco | Pastor, Pau

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) biomarker studies have shown variable accuracy for diagnosis of Alzheimer’s disease (AD); therefore, internal validation is recommended. Objective: To investigate the correlation between CSF biomarkers and cerebral 18-Florbetapir positron emission tomography (Amyloid-PET) and calculate their sensitivity and specificity to obtain the optimal clinical cut-off points to diagnose the etiology of cognitive impairment. Methods: We performed Amyloid-PET scans and CSF biomarker levels analyses in 68 subjects (50 with mild cognitive impairment, 11 with AD dementia, and 7 with non-AD dementia). Visual examination of Amyloid-PET scans was performed. CSF analyses were performed using standard …sandwich ELISA. Results: Amyloid-PET was positive in 36 subjects, negative in 26, and inconclusive in 6. Optimal clinical cut-off points for CSF markers were the following: amyloid-β 1–42 (Aβ42 ) = 629 pg/ml, total tau (t-tau) = 532 pg/ml, phosphorylated tau (p-tau) = 88 pg/ml, and t-tau/Aβ42 ratio = 0.58. T-tau/Aβ42 ratio showed the best sensitivity and specificity (92 and 84%, respectively). T-tau and p-tau CSF levels (r2  = 0.867) followed by the t-tau and t-tau/Aβ42 CSF ratio (r2  = 0.666) showed the strongest inter-marker correlation. Interestingly, subjects with inconclusive Amyloid-PET showed intermediate values for all CSF markers between negative and positive Amyloid-PET groups. Conclusions: CSF t-tau/Aβ42 ratio appears to be the most accurate AD CSF marker. The presence of intermediate values for CSF markers among the subjects with inconclusive Amyloid-PET suggests the presence of other dementias associated with AD pathology or intermediate phenotypes. Show more

Keywords: Alzheimer’s disease, amyloid, apolipoprotein E, cerebrospinal fluid, positron emission tomography

DOI: 10.3233/JAD-170753

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 135-143, 2018

Authors: Kuriyama, Nagato | Ozaki, Etsuko | Mizuno, Toshiki | Ihara, Masafumi | Mizuno, Shigeto | Koyama, Teruhide | Matsui, Daisuke | Watanabe, Isao | Akazawa, Kentaro | Takeda, Kazuo | Takada, Akihiro | Inaba, Masaaki | Yamada, Shinsuke | Motoyama, Koka | Takeshita, Wakiko | Iwai, Komei | Hashiguchi, Kanae | Kobayashi, Daiki | Kondo, Masaki | Tamura, Aiko | Yamada, Kei | Nakagawa, Masanori | Watanabe, Yoshiyuki

Article Type: Research Article

Abstract: Background: The anti-aging protein, α-Klotho, may be involved in cognitive decline and has potential as a surrogate marker that reflects dementia. However, the role of α-Klotho in the brain has not been sufficiently investigated. Objective: Here, we investigated the association between α-Klotho and cognitive decline that is associated with cerebral deep white matter lesions (DWMLs). Methods: Two hundred-eighty participants (187 males and 93 females, mean age: 70.8 years old) were evaluated for DWMLs, and the Fazekas scale (Grade) was assessed following brain magnetic resonance imaging. A questionnaire concerning lifestyle and neuropsychological tests was administered, and their …associations with the blood α-Klotho level were retrospectively investigated. Results: The α-Klotho level was 685.1 pg/mL in Grade 0 (68 subjects), 634.1 in G1 (134), 596.0 in G2 (62), and 571.6 in G3 (16), showing that the level significantly decreased with advanced grades. Significant correlations were noted between the α-Klotho level and higher brain function tests including the Mini-Mental State Examination and word fluency tests (p  < 0.05). When a 90th percentile value of the level in the G0 group (400 pg/mL) or lower was defined as a low α-Klotho level, the odds ratio of the high-grade G3 group was 2.9 (95% confidence interval: 1.4–7.8) (after correction for age, sex, hypertension, and chronic kidney disease), which was significant. Conclusion: A reduced blood α-Klotho level was correlated with grading of cerebral DWMLs and was accompanied by cognitive decline as an independent risk factor. The α-Klotho level may serve as a useful clinical index of vascular cognitive impairment. Show more

Keywords: α-Klotho, deep white matter lesion, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-170466

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 145-155, 2018

Authors: Rosa, Ilka M. | Henriques, Ana G. | Wiltfang, Jens | da Cruz e Silva, Odete A.B.

Article Type: Research Article

Abstract: As the population ages, there is a growing need to quickly and accurately identify putative dementia cases. Many cognitive tests are available; among those commonly used are the Cognitive Dementia Rating (CDR) and the Mini-Mental Status Examination (MMSE). The aim of this work was to compare the validity and reliability of these cognitive tests in a primary care based cohort (pcb-Cohort). The MMSE and the CDR were applied to 568 volunteers in the pcb-Cohort. Distinct cut-off points for the MMSE were considered, namely MMSE 27, MMSE 24, and MMSE PT (adapted for the Portuguese population). The MMSE 27 identified the …greatest number of putative dementia cases, and, as determined by the ROC curve, it was the most sensitive and specific of the MMSE cut-offs considered. Putative predictive or risk factors identified included age, literacy, depression, and diabetes mellitus (DM). DM has previously been indicated as a risk factor for dementia and Alzheimer’s disease. Comparatively, the MMSE 27 cut-off has the greatest sensibility (94.9%) and specificity (66.3%) when compared to MMSE PT and MMSE 24. Upon comparing MMSE and CDR scores, the latter identified a further 146 putative dementia cases, thus permitting one to propose that in an ideal situation, both tests should be employed. This increases the likelihood of identifying putative dementia cases for subsequent follow up work, thus these cognitive tests represent important tools in patient care. Further, this is a significant study for Portuguese populations, where few of these studies have been carried out. Show more

Keywords: Cognitive Dementia Rating, cognitive testing, pcb-Cohort, primary care

DOI: 10.3233/JAD-170501

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 157-167, 2018

Authors: Doecke, James D. | Rembach, Alan | Villemagne, Victor L. | Varghese, Shiji | Rainey-Smith, Stephanie | Sarros, Shannon | Evered, Lisbeth A. | Fowler, Christopher J. | Pertile, Kelly K. | Rumble, Rebecca L. | Trounson, Brett | Taddei, Kevin | Laws, Simon M. | Macaulay, S. Lance | Bush, Ashley I. | Ellis, Kathryn A. | Martins, Ralph | Ames, David | Silbert, Brendan | Vanderstichele, Hugo | Masters, Colin L. | Darby, David G. | Li, Qiao-Xin | Collins, Steven | the AIBL Research Group

Article Type: Research Article

Abstract: Background: To enhance the accuracy of clinical diagnosis for Alzheimer’s disease (AD), pre-mortem biomarkers have become increasingly important for diagnosis and for participant recruitment in disease-specific treatment trials. Cerebrospinal fluid (CSF) biomarkers provide a low-cost alternative to positron emission tomography (PET) imaging for in vivo quantification of different AD pathological hallmarks in the brains of affected subjects; however, consensus around the best platform, most informative biomarker and correlations across different methodologies are controversial. Objective: Assessing levels of Aβ-amyloid and tau species determined using three different versions of immunoassays, the current study explored the ability of CSF biomarkers …to predict PET Aβ-amyloid (32 Aβ-amyloid–and 45 Aβ-amyloid+), as well as concordance between CSF biomarker levels and PET Aβ-amyloid imaging. Methods: Prediction and concordance analyses were performed using a sub-cohort of 77 individuals (48 healthy controls, 15 with mild cognitive impairment, and 14 with AD) from the Australian Imaging Biomarker and Lifestyle study of aging. Results: Across all three platforms, the T-tau/Aβ42 ratio biomarker had modestly higher correlation with SUVR/BeCKeT (ρ = 0.69–0.8) as compared with Aβ42 alone (ρ = 0.66–0.75). Differences in CSF biomarker levels between the PET Aβ-amyloid–and Aβ-amyloid+ groups were strongest for the Aβ42 /Aβ40 and T-tau/Aβ42 ratios (p  < 0.0001); however, comparison of predictive models for PET Aβ-amyloid showed no difference between Aβ42 alone and the T-tau/Aβ42 ratio. Conclusion: This study confirms strong concordance between CSF biomarkers and PET Aβ-amyloid status is independent of immunoassay platform, supporting their utility as biomarkers in clinical practice for the diagnosis of AD and for participant enrichment in clinical trials. Show more

Keywords: Amyloid, biomarker, cerebrospinal fluid, concordance, PET

DOI: 10.3233/JAD-170128

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 169-183, 2018

Authors: Black, Christopher M. | Fillit, Howard | Xie, Lin | Hu, Xiaohan | Kariburyo, M. Furaha | Ambegaonkar, Baishali M. | Baser, Onur | Yuce, Huseyin | Khandker, Rezaul K.

Article Type: Research Article

Abstract: Background: Current information is scarce regarding comorbid conditions, treatment, survival, institutionalization, and health care utilization for Alzheimer’s disease (AD) patients. Objectives: Compare all-cause mortality, rate of institutionalization, and economic burden between treated and untreated newly-diagnosed AD patients. Methods: Patients aged 65–100 years with ≥1 primary or ≥2 secondary AD diagnoses (ICD-9-CM:331.0] with continuous medical and pharmacy benefits for ≥12 months pre-index and ≥6 months post-index date (first AD diagnosis date) were identified from Medicare fee-for-service claims 01JAN2011–30JUN2014. Patients with AD treatment claims or AD/AD-related dementia diagnosis during the pre-index period were excluded. Patients were assigned to …treated and untreated cohorts based on AD treatment received post-index date. Total 8,995 newly-diagnosed AD patients were identified; 4,037 (44.8%) were assigned to the treated cohort. Time-to-death and institutionalization were assessed using Cox regression. To compare health care costs and utilizations, 1 : 1 propensity score matching (PSM) was used. Results: Untreated patients were older (83.85 versus 81.44 years; p  < 0.0001), with more severe comorbidities (mean Charlson comorbidity index: 3.54 versus 3.22; p  < 0.0001). After covariate adjustment, treated patients were less likely to die (hazard ratio[HR] = 0.69; p  < 0.0001) and were associated with 20% lower risk of institutionalization (HR = 0.801; p  = 0.0003). After PSM, treated AD patients were less likely to have hospice visits (3.25% versus 9.45%; p  < 0.0001), and incurred lower annual all-cause costs ($25,828 versus $30,110; p  = 0.0162). Conclusion: After controlling for comorbidities, treated AD patients have better survival, lower institutionalization, and sometimes fewer resource utilizations, suggesting that treatment and improved care management could be beneficial for newly-diagnosed AD patients from economic and clinical perspectives. Show more

Keywords: Alzheimer’s disease, institutionalization, Medicare, mortality

DOI: 10.3233/JAD-170518

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 185-193, 2018

Authors: Gelman, Simon | Palma, Jonathan | Tombaugh, Geoffrey | Ghavami, Afshin

Article Type: Research Article

Abstract: Genetically modified mice have provided insights into the progression and pathology of Alzheimer’s disease (AD). Here, we have examined two mouse models of AD: the rTg4510 mouse, which overexpresses mutant human Tau gene, and the APP/PS1 mouse, which overexpresses mutant human genes for amyloid precursor protein and presenilin 1. Both models exhibit deficits in hippocampal function, but comparative analyses of these deficits are sparse. We used extracellular field potential recordings in hippocampal slices to study basal synaptic transmission (BST), paired-pulse facilitation (PPF), and long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapses in both models. We found that 6-7, …but not 2-3-month-old rTg4510 mice exhibited reduced pre-synaptic activation (fiber volley (FV) amplitude, ∼50%) and field excitatory post-synaptic potential (fEPSP) slope (∼40%) compared to wild-type controls. In contrast to previous reports, BST, when controlled for FV amplitude, was not altered in rTg4510. APP/PS1 mice (2-3 mo and 8-10 mo) had unchanged FV amplitude compared to wild-type controls, while fEPSP slope was reduced by ∼34% in older mice, indicating a deficit in BST. PPF was unchanged in 8–10-month-old APP/PS1 mice, but was reduced in 6-7-month-old rTg4510 mice. LTP was reduced only in older rTg4510 and APP/PS1 mice. Our data suggest that BST deficits appear earlier in APP/PS1 than in rTg4510, which exhibited no BST deficits at the ages tested. However, FV and synaptic plasticity deficits developed earlier in rTg4510. These findings highlight fundamental differences in the progression of synaptic pathology in two genetically distinct models of AD. Show more

Keywords: Amyloidosis, electrophysiology, synaptic dysfunction, tauopathy

DOI: 10.3233/JAD-170457

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 195-208, 2018

Authors: Villamil-Ortiz, Javier Gustavo | Barrera-Ocampo, Alvaro | Arias-Londoño, Julián David | Villegas, Andrés | Lopera, Francisco | Cardona-Gómez, Gloria Patricia

Article Type: Research Article

Abstract: Lipids are considered important factors in the pathogenesis of Alzheimer’s disease (AD). In this study, we realized a comparative analysis of the phospholipid profile and phospholipid composition of the temporal cortex from E280A-familiar AD (FAD), sporadic AD (SAD), and healthy human brains. Findings showed a significant decrease of lysophosphatidylcholine and phosphatidylethanolamine formed by low levels of polyunsaturated fatty acids (20 : 4, 22 : 6) in AD brains. However, phosphatidylethanolamine-ceramide and phosphoglycerol were significantly increased in SAD, conformed by high levels of (18 : 0/18 : 1) and (30/32/36 : 0/1/2), respectively. Together, the findings suggest a deficiency in lysophosphacholine and phosphatidylethanolamine, and alteration in the balance between poly- and …unsaturated fatty acids in both types of AD, and a differential pattern of phospholipid profile and fatty acid composition between E280A FAD and SAD human brains. Show more

Keywords: Alzheimer’s disease, phospholipids, fatty acids, temporal cortex, polyunsaturated fatty acids

DOI: 10.3233/JAD-170554

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 209-219, 2018

Authors: Muthukumaran, Krithika | Kanwar, Annie | Vegh, Caleb | Marginean, Alexandra | Elliott, Austin | Guilbeault, Nicholas | Badour, Alexander | Sikorska, Marianna | Cohen, Jerome | Pandey, Siyaram

Article Type: Research Article

Abstract:  Alzheimer’s disease (AD) is one of the most common neurodegenerative pathologies for which there are no effective therapies to halt disease progression. Given the increase in the incidence of this disorder, there is an urgent need for pharmacological intervention. Unfortunately, recent clinical trials produced disappointing results. Molecular mechanisms of AD are converging on the notion that mitochondrial dysfunction, oxidative stress, and accumulation of dysfunctional proteins are involved in AD pathology. Previously, we have shown that a water-soluble formulation of Coenzyme Q10 (Ubisol-Q10 ), an integral part of the electron transport chain, stabilizes mitochondria and prevents neuronal cell death caused …by neurotoxins or oxidative stress both in vitro and in vivo . In this study, we evaluated the neuroprotective effects of Ubisol-Q10 treatment in double transgenic AD mice. In the present study, we report that providing Ubisol-Q10 in drinking water (at a dose of ∼6 mg/kg/day) reduced circulating amyloid-β (Aβ) peptide, improved long term memory, preserved working spatial memory, and drastically inhibited Aβ plaque formation in 18-month-old transgenic mice compared to an untreated transgenic group. Thus Ubisol-Q10 supplementation has the potential to inhibit the progression of neurodegeneration, leading to a better quality of life for humans suffering with AD. Show more

Keywords: Alzheimer’s disease, amyloid-β plaques, CoQ10, long term memory, working memory

DOI: 10.3233/JAD-170275

Citation: Journal of Alzheimer's Disease, vol. 61, no. 1, pp. 221-236, 2018