Journal of Alzheimer's Disease - Volume 52, issue 3

Authors: Jayne, Tanya | Newman, Morgan | Verdile, Giuseppe | Sutherland, Greg | Münch, Gerald | Musgrave, Ian | Moussavi Nik, Seyyed Hani | Lardelli, Michael

Article Type: Review Article

Abstract: The majority of mutations causing familial Alzheimer’s disease (fAD) have been found in the gene PRESENILIN1 (PSEN1 ) with additional mutations in the related gene PRESENILIN2 (PSEN2 ). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (A βPP/APP ) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in …a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the “fAD mutation reading frame preservation rule” that applies to PSEN1 and PSEN2 (and A βPP ) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a “PSEN holoprotein multimer hypothesis” where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs’ γ-secretase activity. Show more

Keywords: Amyloid precursor protein secretases, familial Alzheimer’s disease, gamma-secretase, human APP protein, human PSEN1 protein, human PSEN2 protein

DOI: 10.3233/JAD-151186

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 781-799, 2016

Authors: Lopes, Jéssica | Correia, Marta | Martins, Ilka | Henriques, Ana Gabriela | Delgadillo, Ivonne | da Cruz e Silva, Odete | Nunes, Alexandra

Article Type: Review Article

Abstract: To date, it is still difficult to perform an early and accurate diagnosis of dementia, therefore significant research has focused on finding new dementia biomarkers that can aid in this respect. There is an urgent need for non-invasive, rapid, and relatively inexpensive procedures for early diagnostics. Studies have demonstrated that of spectroscopic techniques, such as Fourier Transform Infrared Spectroscopy (FTIR) and Raman Spectroscopy could be a useful and accurate procedure to diagnose dementia. Given that several biochemical mechanisms related to neurodegeneration and dementia can lead to changes in plasma components and others peripheral body fluids; blood-based samples coupled to spectroscopic …analyses can be used as a simple and less invasive approach. Show more

Keywords: Alzheimer’s disease, blood-based biomarkers, dementia diagnosis, disease fingerprint, Fourier Transform Infrared Spectroscopy, metabolomic approach, Raman Spectroscopy, vibrational spectroscopy

DOI: 10.3233/JAD-151163

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 801-812, 2016

Authors: Zeng, Lingfeng | Liang, Weixiong | Pan, Jianke | Cao, Ye | Liu, Jun | Wang, Qi | Wang, Lu | Zou, Yuanping | Wang, Kezhu | Kong, Lingshuo | Xie, Hui | Xu, Weihua | Li, Weirong | Zhao, Wei | Mi, Suiqing | Chen, Yunbo | Cheng, Shuyi | Li, Xiaoyan | Cao, Qian | Zeng, Xing | Wang, Ningsheng

Article Type: Review Article

Abstract: Background: Medical research using human participants must conform to the basic ethical principles found in the Declaration of Helsinki (DoH) of the World Medical Association. Objective: The purpose of this review was to assess whether journals in China have improved in regard to the fulfillment of ethical disclosure procedures for clinical trials of anti-dementia drugs. Methods: Four medical databases were searched for articles reporting clinical trials of oral anti-dementia drugs published in China in 2003, 2009, and 2014. The frequencies of reporting of informed consent from participants (ICP), approval of a regional ethical committee (REC), …reference to DoH, and study registration were estimated respectively. Statistical analyses were conducted with SPSS v21 software. Results: Among those randomized controlled trials published in 2003, 2009, and 2014, disclosure of REC approval was present for 2.67%, 1.15%, and 6.84%; statements of ICP were included in 9.33%, 7.76%, and 17.34%; reference to DoH was found for 4.00%, 1.44%, and 7.45%; and study registration reporting was included in 2.67%, 2.59%, and 9.28%, respectively. Improvements to reporting rates between 2009 and 2014 were seen, with more than twice as many trials reporting REC approval, ICP, reference to DoH, and study registration compared with 2009. Conclusion: Compared with 2003 and 2009, reporting rates for REC approval, ICP, reference to DoH, and study registration for clinical trials of anti-dementia drugs were enhanced in 2014 in the major medical journals of China. However, biomedical publications without definite statements of ethical considerations remain common, and this continues to be seen in Chinese journals. It is imperative that measures are taken to reinforce the ethical protection in clinical trials in China. Show more

Keywords: Anti-dementia drugs, clinical trials, ethical protection, ICP, REC

DOI: 10.3233/JAD-150858

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 813-823, 2016

Authors: Rosenberg, Jacob

Article Type: Research Article

Abstract: Zeng et al.’s Ethics Review highlights some of the challenges associated with clinical research in China. They found that only a minority of published clinical trials of anti-dementia drugs reported that they fulfilled the basic ethical principles as outlined in the Declaration of Helsinki. With recent reports of scientific misconduct from China, there is an urgent need to find approaches to compel researchers to adhere to ethical research practices. This problem does not call for a simple solution, but if forces are joined with governmental regulations, education in ethics issues for medical researchers, and strong reinforcement by Chinese journal editors …not to publish studies with these flaws, then research ethics and publication standards will probably improve. Other solutions to foster ethical practice of drug trials are discussed including Chinese initiatives directed at managing conflict of interest from the pharmaceutical industry and educating clinical researchers. Show more

Keywords: Research ethics, Helsinki declaration, informed consent

DOI: 10.3233/JAD-151196

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 825-827, 2016

Authors: Wang, Ningsheng | Zeng, Lingfeng | Zeng, Xing | Liu, Jun | Liang, Weixiong | Wang, Qi

Article Type: Research Article

DOI: 10.3233/JAD-160075

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 829-830, 2016

Authors: Sekiyama, Kazunari | Takamatsu, Yoshiki | Koike, Wakako | Waragai, Masaaki | Takenouchi, Takato | Sugama, Shuei | Hashimoto, Makoto

Article Type: Research Article

Abstract: Recent clinical trials using immunization approaches against Alzheimer’s disease (AD) have failed to demonstrate improved cognitive functions in patients, despite potent suppression in the formation of both senile plaques and other amyloid-β deposits in postmortem brains. Similarly, we observed that treatment with ibuprofen, a non-steroidal anti-inflammatory drug, was effective in improving the histopathology, such as reducing both protein aggregation and glial activation, in the brains of transgenic mice expressing dementia with Lewy bodies-linked P123H β-synuclein. In contrast, only a small improvement in cognitive functions was observed in these mice. Collectively, it is predicted that histology does not correlate with behavior …that is resilient and resistant to therapeutic stimuli. Notably, such a ‘discrepancy between histology and behavior’ is reminiscent of AD-like pathologies and incidental Lewy bodies, which are frequently encountered in postmortem brains of the elderly who had been asymptomatic for memory loss and Parkinsonism during their lives. We suggest that ‘the discrepancy between histology and behavior’ may be a universal feature that is associated with various aspects of neurodegenerative diseases. Furthermore, given that the cognitive reserve is specifically observed in human brains, human behavior may be evolutionally distinct from that in other animals, thus, contributing to the differential efficiency of therapy between human and lower animals, an important issue in the therapy of neurodegenerative diseases. Overall, it is important to better understand ‘the discrepancy between histology and behavior’ in the mechanism of neurodegeneration for the development of effective therapies against neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, adiponectin, behavior, cognitive function, cognitive reserve, dementia with Lewy bodies, ibuprofen, histology, neurodegenerative disease, protofibrils

DOI: 10.3233/JAD-151015

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 831-841, 2016

Authors: Miller, Brendan J. | Whisner, Corrie M. | Johnston, Carol S.

Article Type: Short Communication

Abstract: Low plasma amyloid-β (Aβ) is linked to Alzheimer’s disease. Since vitamin D cleared brain Aβ in vitro , this 8-week trial examined whether vitamin D increased plasma Aβ40 . Vitamin D insufficient adults (6/18 M/F; 64.3 ± 10.9 y) were randomized to placebo or vitamin (50,000 IU/week) treatments. The vitamin group experienced greater plasma Aβ40 change than controls, +14.9 ± 12.0 and +12.8 ± 12.8 pg/mL (p  = 0.045; effect size, 0.228). Change in Aβ40 for older participants (≥60 y) was +18.3 ± 33.6 and –3.2 ± 44.5 pg/mL for vitamin (n  = 4) and placebo (n  = 4) groups (effect …size, 0.295). Thus, vitamin D may increase plasma Aβ, particularly in older adults, suggesting decreased brain Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, P-glycoprotein, plasma Aβ, vitamin D

DOI: 10.3233/JAD-150901

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 843-847, 2016

Authors: Bangen, Katherine J. | Clark, Alexandra L. | Werhane, Madeline | Edmonds, Emily C. | Nation, Daniel A. | Evangelista, Nicole | Libon, David J. | Bondi, Mark W. | Delano-Wood, Lisa | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: We examined cortical amyloid-β (Aβ) levels and interactions with apolipoprotein (APOE) ɛ 4 genotype status across empirically-derived mild cognitive impairment (MCI) subgroups and cognitively normal older adults. Participants were 583 ADNI participants (444 MCI, 139 normal controls [NC]) with baseline florbetapir positron emission tomography (PET) amyloid imaging and neuropsychological testing. Of those with ADNI-defined MCI, a previous cluster analysis [1 ] classified 51% (n  = 227) of the current sample as amnestic MCI, 8% (n  = 37) as dysexecutive/mixed MCI, and 41% (n  = 180) as cluster-derived normal (cognitively normal). Results demonstrated that the dysexecutive/mixed and amnestic MCI groups showed significantly greater levels …of amyloid relative to the cluster-derived normal and NC groups who did not differ from each other. Additionally, 78% of the dysexecutive/mixed, 63% of the amnestic MCI, 42% of the cluster-derived normal, and 34% of the NC group exceeded the amyloid positivity threshold. Finally, a group by APOE genotype interaction demonstrated that APOE ɛ 4 carriers within the amnestic MCI, cluster-derived normal, and NC groups showed significantly greater amyloid accumulation compared to non-carriers of their respective group. Such an interaction was not revealed within the dysexecutive/mixed MCI group which was characterized by both greater cognitive impairment and amyloid accumulation compared to the other participant groups. Our results from the ADNI cohort show considerable heterogeneity in Aβ across all groups studied, even within a group of robust NC participants. Findings suggest that conventional criteria for MCI may be susceptible to false positive diagnostic errors, and that onset of Aβ accumulation may occur earlier in APOE ɛ 4 carriers compared to non-carriers. Show more

Keywords: Amyloid, apolipoprotein E, APOE, biomarkers, florbetapir, mild cognitive impairment, neuroimaging, neuropsychology, PET, positron emission tomography

DOI: 10.3233/JAD-150900

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 849-861, 2016

Authors: Beach, Thomas G. | Thal, Dietmar Rudolf | Zanette, Michelle | Smith, Adrian | Buckley, Christopher

Article Type: Research Article

Abstract: Amyloid imaging is limited by an inconsistent relationship between cerebral cortex amyloid- β (Aβ) plaques and dementia. Autopsy studies suggest that Aβ plaques first appear in the cerebral cortex while subcortical plaques are present only later in the disease course. The presence of abundant plaques in both cortex and striatum is more strongly correlated with the presence of dementia than cortical Aβ plaques alone. Additionally, detection of striatal plaques may allow, for the first time, pathology-based clinical staging of AD. Striatal plaques are reportedly identifiable by amyloid imaging but the accuracy and reliability of striatal amyloid imaging has never been …tested against postmortem histopathology. To determine this, we correlated the presence of histopathologically-demonstrated striatal Aβ deposits with a visually positive panel consensus decision of a positive [18 F]flutemetamol striatal PET signal in 68 subjects that later came to autopsy. The sensitivity of [18 F]flutemetamol PET striatal amyloid imaging, for several defined density levels of histological striatal Aβ deposits, ranged between 69% and 87% while the specificity ranged between 96% and 100%. Sensitivity increased with higher histological density thresholds while the reverse was found for specificity. In general, as compared with PET alone, PET with CT had slightly higher sensitivities but slightly lower specificities. In conclusion, amyloid imaging of the striatum with [18 F]flutemetamol PET has reasonable accuracy for the detection of histologically-demonstrated striatal Aβ plaques when present at moderate or frequent densities. Amyloid imaging of the cerebral cortex and striatum together may allow for a more accurate clinicopathological diagnosis of AD and enable pathology-based clinical staging of AD. Show more

Keywords: Alzheimer’s disease, amyloid imaging, autopsy, diagnosis, [18F]flutemetamol, preclinical, staging

DOI: 10.3233/JAD-150732

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 863-873, 2016

Authors: Handels, Ron L.H. | Joore, Manuela A. | Vos, Stephanie J.B. | Aalten, Pauline | Ramakers, Inez H.G.B. | Rikkert, Marcel Olde | Scheltens, Philip | Jansen, Willemijn J. | Visser, Pieter-Jelle | van Berckel, Bart M.N. | van Domburg, Peter | Smid, Machiel | Hoff, Erik | Hoogmoed, Jan | Bouwman, Femke | Claassen, Jurgen | Leentjens, Albert F.G. | Wolfs, Claire A.G. | Severens, Johan L. | Verhey, Frans R.J.

Article Type: Research Article

Abstract: Background: Limited information is available on short-term prognosis of Alzheimer’s disease (AD) biomarkers in cerebrospinal fluid (CSF) in addition to routine diagnostic workup. Objective: This study aims to investigate the added prognostic value of AD CSF biomarkers. Methods: In a prospective cohort study, clinical experts predicted cognitive and functional symptoms in 114 memory clinic patients by assessing comprehensive routine diagnostic test information (patient history, and physical, neurological, psychiatric, neuropsychological, and MRI examinations), without and with CSF biomarkers. The reference standard was the ‘observed clinically relevant decline’ using baseline and 1- and 2-year follow-up information. …Results: Decline over a 2-year period was observed in 51% of all participants (3% in SMC, 48% in MCI, 90% in mild dementia). In the total sample, the accuracy of predicted decline did not differ significantly between routine assessment without (79% correctly predicted) and with (74% correctly predicted) CSF biomarkers. Subgroup analyses revealed 25 (83%) correct predictions in SMC, 30 (68%) in MCI, and 35 (88%) in dementia without the use of CSF; and 21 (70%), 27 (61%), and 36 (90%), respectively, with the use of CSF in addition to the routine assessment. Conclusion: AD CSF biomarkers did not increase accuracy of 2-year prognosis of cognitive and functional decline when added to routine diagnostic workup. This suggests that the standard diagnostic workup without CSF biomarkers allows fairly accurate predictions for the short-term course of symptoms. Routine AD biomarkers in CSF have limited prognostic value over 2 years in persons with a suspected cognitive disorder. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, memory disorders, mild cognitive impairment, prognosis, sensitivity and specificity

DOI: 10.3233/JAD-151120

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 875-885, 2016