Journal of Alzheimer's Disease - Volume 53, issue 4

Authors: Glonnegger, Hannah | Beyle, Aline | Cerff, Bernhard | Gräber, Susanne | Csoti, Ilona | Berg, Daniela | Liepelt-Scarfone, Inga

Article Type: Research Article

Abstract: Background: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson’s disease (PD). Objective: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. Methods: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson’s disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive …cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. Results: Total time and number of MOT errors was increased in PD patients compared to controls (p  < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p  < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p  < 0.001) and mislocation (p  < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p  = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. Conclusion: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD. Show more

Keywords: Activities of daily living, cognition, dementia, Parkinson’s disease, performance-based assessment

DOI: 10.3233/JAD-160173

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1475-1484, 2016

Authors: Stravalaci, Matteo | Tapella, Laura | Beeg, Marten | Rossi, Alessandro | Joshi, Pooja | Pizzi, Erika | Mazzanti, Michele | Balducci, Claudia | Forloni, Gianluigi | Biasini, Emiliano | Salmona, Mario | Diomede, Luisa | Chiesa, Roberto | Gobbi, Marco

Article Type: Research Article

Abstract: 15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42 , an aggregating peptide implicated in the pathogenesis of Alzheimer’s disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans ; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers …in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD. Show more

Keywords: 15B3 antibody, Alzheimer’s disease, amyloid beta-protein (1– 42), oligomers, prion protein, prions, oligomers

DOI: 10.3233/JAD-150882

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1485-1497, 2016

Authors: Qosa, Hisham | Mohamed, Loqman A. | Al Rihani, Sweilem B. | Batarseh, Yazan S. | Duong, Quoc-Viet | Keller, Jeffrey N. | Kaddoumi, Amal

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate …inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76–4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD. Show more

Keywords: Amyloid-β , blood-brain barrier, high-throughput screening, permeability, repurposing

DOI: 10.3233/JAD-151179

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1499-1516, 2016

Authors: Grossi, Enzo | Stoccoro, Andrea | Tannorella, Pierpaola | Migliore, Lucia | Coppedè, Fabio

Article Type: Research Article

Abstract: Background: There is increasing interest in DNA methylation studies in Alzheimer’s disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients. Objective: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1 , BACE1 , DNMT1 , DNMT3A , DNMT3B , and MTHFR genes in blood DNA. Methods: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals. Results: Low vitamin …B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes. Conclusions: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12. Show more

Keywords: Alzheimer’s disease, BACE1, DNA methylation, DNMT, folate, homocysteine, MTHFR, PSEN1, vitamin B12

DOI: 10.3233/JAD-160210

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1517-1522, 2016

Authors: De Vos, Ann | Struyfs, Hanne | Jacobs, Dirk | Fransen, Erik | Klewansky, Tom | De Roeck, Ellen | Robberecht, Caroline | Van Broeckhoven, Christine | Duyckaerts, Charles | Engelborghs, Sebastiaan | Vanmechelen, Eugeen

Article Type: Research Article

Abstract: Background: In diagnosing Alzheimer’s disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42 /tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42 , Aβ1-40 , and Aβ1-38 . All six analytes were considered as single parameters as well as ratios. …Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n  = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n  = 20). A significant subset of the patients was followed up by clinical and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline. Show more

Keywords: Alzheimer’s disease, BACE1 protein, biomarkers, cerebrospinal fluid, ELISA, mild cognitive impairment, neurogranin, prognostic, ratio

DOI: 10.3233/JAD-160227

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1523-1538, 2016

Authors: Han, Bing | Yu, Lulu | Geng, Yuan | Shen, Li | Wang, Hualong | Wang, Yanyong | Wang, Jinhua | Wang, Mingwei

Article Type: Research Article

Abstract: Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, …neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer’s disease in vulnerable individuals. Show more

Keywords: Alzheimer’s disease, cognitive function, hippocampus, insulin sensitivity, stress, transgenic animals

DOI: 10.3233/JAD-160189

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1539-1552, 2016

Authors: Bangen, Katherine J. | Himali, Jayandra J. | Beiser, Alexa S. | Nation, Daniel A. | Libon, David J. | Fox, Caroline S. | Seshadri, Sudha | Wolf, Philip A. | McKee, Ann C. | Au, Rhoda | Delano-Wood, Lisa

Article Type: Research Article

Abstract: Elevated blood glucose and the apolipoprotein (APOE) ɛ 4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer’s disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ 4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship …with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ 4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment. Show more

Keywords: Alzheimer’s disease, apolipoprotein E (APOE), diabetes, glucose, neuropathology, vascular risk

DOI: 10.3233/JAD-160163

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1553-1562, 2016

Authors: Kang, Seokjo | Jeong, Hyobin | Baek, Je-Hyun | Lee, Seung-Jin | Han, Sun-Ho | Cho, Hyun Jin | Kim, Hee | Hong, Hyun Seok | Kim, Young Ho | Yi, Eugene C. | Seo, Sang Won | Na, Duk L. | Hwang, Daehee | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Development of a simple, non-invasive early diagnosis platform of Alzheimer’s disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 …differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD. Show more

Keywords: Alzheimer’s disease, biomarker, LC-MS/MS, mild cognitive impairment, proteomics, serum

DOI: 10.3233/JAD-160025

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1563-1576, 2016

Authors: Li, Xudong | Jia, Shuhong | Zhou, Zhi | Hou, Chunlei | Zheng, Wenjing | Rong, Pei | Jiao, Jinsong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder. Objectives: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI). Methods: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR). Results: …Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p  < 0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p  < 0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p  = 0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r  = 0.637, p  < 0.001), the MoCA (r  = 0.572, p  < 0.001), and the CDT (r  = 0.514, p  < 0.001) and were negatively correlated with the CDR scores (r  = –0.558, p  < 0.001). Conclusions: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics. Show more

Keywords: Alzheimer’s disease, gesture imitation, mild cognitive impairment, neuropsychological test

DOI: 10.3233/JAD-160218

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1577-1584, 2016

Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. Objective: We aimed to assess the predictive validity of the MBT for incident aMCI. Methods: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score …of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. Results: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30–4.56, p  = 0.005). When varying the prediction window from 4–7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33–3.12, p : 0.0007–0.04). Conclusion: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, longitudinal studies, memory, mild cognitive impairment, preclinical, survival analysis

DOI: 10.3233/JAD-160291

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1585-1595, 2016