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

Authors: Vercambre, Marie-Noël | Okereke, Olivia I. | Kawachi, Ichiro | Grodstein, Francine | Kang, Jae H.

Article Type: Research Article

Abstract: To investigate whether a positive transition into retirement may be associated with later cognitive aging, we included a subset of 4,926 Nurses’ Health Study participants who retired from work at ages 60–69, then provided a subjective assessment of the change in overall quality of life (QOL) with retirement. Subsequently (range: 1 month to 4.7 years later), when all were aged 70+ years, they completed a baseline telephone cognitive battery evaluating global cognition, episodic memory, and executive function. They had up to three follow-up cognitive assessments. Controlling for various occupational factors before retirement and socioeconomic, lifestyle, and health-related factors as of …the baseline cognitive assessment, we used generalized linear models for repeated measures to estimate mean differences in rates of cognitive decline across categories of QOL transition at retirement: “worse”, “same”, or “better”. Over a median 6 years of follow-up, the global cognitive score change was –0.123 on average. Compared with women who reported no change in QOL at retirement (31%), women who reported improvement (61%) showed a significantly slower rate of cognitive decline (difference = +0.011 95% CI = 0.004, 0.019). This mean difference was equivalent to that observed between women who were 2 years apart in age. No significant differences in cognitive decline rates were observed for the women who reported worsened QOL (8%). Secondary analyses to address possible reverse causation showed robust associations. A positive transition into retirement was associated with better maintenance of cognitive function over time in aging women. These findings need to be replicated in other populations. Show more

Keywords: Aging, cognition, cohort studies, epidemiology, quality of life, retirement

DOI: 10.3233/JAD-150867

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 887-898, 2016

Authors: Huang, Han-Chang | Zheng, Bo-Wen | Guo, Yu | Zhao, Jian | Zhao, Jiang-Yan | Ma, Xiao-Wei | Jiang, Zhao-Feng

Article Type: Research Article

Abstract: Epidemiological data imply links between the increasing incidences of Alzheimer’s disease (AD) and type 2 diabetes mellitus. In this study, an AD rat model was established by combining treatments with intracerebroventricular streptozotocin (icv-STZ) and subcutaneous D-galactose, and the effects of curcumin on depressing AD-like symptoms were investigated. In the AD model group, rats were treated with icv-STZ in each hippocampus with 3.0 mg/kg of bodyweight once and then were subcutaneously injected with D-galactose daily (125 mg/kg of bodyweight) for 7 weeks. In the curcumin-protective group, after icv-STZ treatment, rats were treated with D-galactose (the same as in the AD model group) and …intraperitoneally injected with curcumin daily (10 mg/kg of bodyweight) for 7 weeks. Vehicle-treated rats were treated as control. Compared with the vehicle control, the amount of protein carbonylation and glutathione in liver, as well as malondialdehyde in serum, were upregulated but glutathione peroxidase activity in blood was downregulated in the AD model group. The shuttle index and locomotor activity of rats in the AD model group were decreased compared with the vehicle control group. Furthermore, AD model rats showed neuronal damage and neuron loss with formation of amyloid-like substances and neurofibrillary tangles, and the levels of both β-cleavage of AβPP and phosphorylation of tau (Ser396) were significantly increased compared with the vehicle control group. Notably, compared with the AD model group, oxidative stress was decreased and the abilities of active avoidance and locomotor activity were improved, as well as attenuated neurodegeneration, in the curcumin-protective group. These results imply the applications of this animal model for AD research and of curcumin in the treatment of AD. Show more

Keywords: Alzheimer’s disease, animal model, curcumin, D-galactose, neurodegeneration, streptozotocin

DOI: 10.3233/JAD-150872

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 899-911, 2016

Authors: Zhan, Yafeng | Ma, Jianhua | Alexander-Bloch, Aaron F. | Xu, Kaibin | Cui, Yue | Feng, Qianjin | Jiang, Tianzi | Liu, Yong | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is associated with abnormal resting-state network (RSN) architecture of the default mode network (DMN), the dorsal attention network (DAN), the executive control network (CON), the salience network (SAL), and the sensory-motor network (SMN). However, little is known about the disrupted intra- and inter-network architecture in mild cognitive impairment (MCI). Here, we employed a priori defined regions of interest to investigate the intra- and inter-network functional connectivity profiles of these RSNs in longitudinal participants, including normal controls (n  = 23), participants with early MCI (n  = 26), and participants with late MCI (n  = 19). We found longitudinal alterations of …functional connectivity within the DMN, where they were correlated with variation in cognitive ability. The SAL as well as the interaction between the DMN and the SAL were disrupted in MCI. Furthermore, our results demonstrate that longitudinal alterations of functional connectivity are more profound in earlier stages as opposed to later stages of the disease. The increased severity of cognitive impairment is associated with increasingly altered RSN connectivity patterns, suggesting that disruptions in functional connectivity may contribute to cognitive dysfunction and may represent a potential biomarker of impaired cognitive ability in MCI. Earlier prevention and treatment may help to delay disease progression to AD. Show more

Keywords: Default mode network, early mild cognitive impairment, late mild cognitive impairment, resting-state network, salience network

DOI: 10.3233/JAD-160008

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 913-927, 2016

Authors: Vandepitte, Sophie | Van Den Noortgate, Nele | Putman, Koen | Verhaeghe, Sofie | Faes, Kristof | Annemans, Lieven

Article Type: Research Article

Abstract: Background: Dementia is known as a major public health problem affecting both patients and caregivers, and placing a high financial strain upon society. In community-dwelling patients, it is important to support informal caregivers in order to help them sustain their demanding role. Previous reviews about effectiveness of such supporting strategies often included a small number of studies, focused only on particular supportive types, particular outcomes, or solely on caregivers. Objective: A general systematic review was conducted investigating effectiveness of different supportive strategies on at least the well-being of the caregiver or the care-recipient. Methods: A …systematic literature search was conducted in Web of Science and PubMed. An adapted version of the Downs and Black (1998) checklist was used to assess methodological quality. A new classification was developed to group different types of caregiver support. Results: Fifty-three papers met the inclusion criteria. Although 87% of the interventions were to some extent effective, methods and findings were rather inconsistent. Psychoeducational interventions generally lead to positive outcomes for caregivers, and delay permanent institutionalization of care-recipients. Cognitive behavioral therapy decreases dysfunctional thoughts among caregivers. Occupational therapy decreases behavioral problems among patients and improves self-efficacy of caregivers. In general, those interventions tailored on individual level generate better outcomes. Comparative research on respite care was very rare. Conclusions: Despite methodological inconsistency, supporting caregivers appears to be an effective strategy often improving well-being of caregiver or care-recipient and resulting in additional benefits for society. However, there is a need for more research on the (cost)-effectiveness of respite care. Show more

Keywords: Alzheimer’s disease, caregiver, dementia, effectiveness, support

DOI: 10.3233/JAD-151011

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 929-965, 2016

Authors: Connors, Michael H. | Ames, David | Boundy, Karyn | Clarnette, Roger | Kurrle, Sue | Mander, Alastair | Ward, John | Woodward, Michael | Brodaty, Henry

Article Type: Research Article

Abstract: Background: Dementia is a terminal illness. While various baseline characteristics of patients, such as age, sex, and dementia severity, are known to predict mortality, little research has examined how changes in patients’ symptoms over time predict survival. There are also limited data on patients seen in memory clinics, as opposed to other health care settings, and whether antipsychotic medications are associated with mortality in dementia once patients’ demographic and clinical features are controlled for. Objective: To identify predictors of mortality in patients with dementia. Method: Of 970 patients recruited from nine memory clinics around Australia, …779 patients had dementia at baseline. Patients completed measures of dementia severity, cognition, functional ability, neuropsychiatric symptoms, caregiver burden, and medication use at baseline and at regular intervals over a three-year period. Mortality data were obtained from state registries eight years after baseline. Results: Overall, 447 (57.4%) of the patients with dementia died within the eight years. Older age, male sex, more severe dementia and functional impairment at baseline, greater decline in dementia severity and functional impairment over six months, taking a larger number of medications, and use of atypical antipsychotic medication predicted earlier mortality. Conclusions: The findings confirm that demographic and diagnostic features predict the survival of patients with dementia. Importantly, the findings indicate that changes in dementia severity and functional impairment over time predict mortality independently of baseline levels, and provide further evidence for the higher mortality risk of patients taking antipsychotic medications. Show more

Keywords: Death, dementia, longitudinal study, mortality, predictors

DOI: 10.3233/JAD-150946

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 967-974, 2016

Authors: Colin, Julie | Allouche, Ahmad | Chauveau, Fabien | Corbier, Catherine | Pauron-Gregory, Lynn | Lanhers, Marie-Claire | Claudepierre, Thomas | Yen, Frances T. | Oster, Thierry | Malaplate-Armand, Catherine

Article Type: Research Article

Abstract: Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer’s disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with …Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n -3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment. Show more

Keywords: Alzheimer’s disease, cell-generated Aβ peptide, neuronal apoptosis, neuroprotection, oxidative stress, synaptic proteins

DOI: 10.3233/JAD-151110

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 975-987, 2016

Authors: Iaccarino, Leonardo | Marelli, Sara | Iannaccone, Sandro | Magnani, Giuseppe | Ferini-Strambi, Luigi | Perani, Daniela

Article Type: Research Article

Abstract: Background/Objective: To evaluate the prevalence of REM sleep behavior disorder (RBD) in a sample of Dementia with Lewy Bodies (DLB) and Alzheimer’s Disease (AD) patients and compare the patterns of brain glucose metabolism in DLB patients with or without the sleep disturbances. Methods: In this retrospective study, the presence of probable RBD was ascertained for 27 clinically diagnosed DLB patients and 11 AD patients by a self-administered RBD Single-Question Screen (RBD1Q), followed by a sleep structured interview by experts in sleep disorders blinded to clinical information. For 18 F-FDG-PET metabolic comparisons, we considered an additional 13 DLB …patients with negative history for sleep disturbance. We performed DLB within-group comparisons covarying for age and disease duration. Results: The RBD1Q questionnaire identified 20 out of 27 DLB RBD+ and 7 out of 27 DLB RBD–. None of the AD patients was positive to RBD1Q test. 18 F-FDG-PET hypometabolism at the single- and group-level tested by means of an optimized SPM approach revealed the typical DLB metabolic pattern. Each DLB patient showed a predominant occipital hypometabolism. The SPM voxel-based comparisons revealed significant brain metabolic differences, namely a more severe metabolic decrease in DLB RBD+ in the dorsolateral and medial frontal regions, left precuneus, bilateral superior parietal lobule and rolandic operculum, and amygdala. Discussion: We found a high prevalence of RBD in DLB and none in AD, as identified by the RBD1Q questionnaire, indicating its utility in clinical practice. DLB patients with or without RBD show different hypometabolism patterns that might reflect differences in underlying pathology. Show more

Keywords: Brain metabolism, dementia, dementia with Lewy bodies, 18F-FDG-PET, REM sleep behavior disorder, sleep

DOI: 10.3233/JAD-151000

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 989-997, 2016

Authors: Conde-Sala, Josep L. | Turró-Garriga, Oriol | Portellano-Ortiz, Cristina | Viñas-Diez, Vanesa | Gascón-Bayarri, Jordi | Reñé-Ramírez, Ramón

Article Type: Research Article

Abstract: The objective was to analyze the factors that influence self-perceived quality of life (QoL) in patients with Alzheimer’s disease (AD), contrasting two different longitudinal models. A total of 127 patients were followed up over 24 months. The instruments applied were: Quality of Life in Alzheimer’s Disease scale (QoL-AD), Geriatric Depression Scale-15, Anosognosia Questionnaire-Dementia, Disability Assessment in Dementia, Neuropsychiatric Inventory, and the Mini-Mental State Examination. Two models for grouping patients were tested: 1) Baseline score on the QoL-AD (QoL-Baseline), and 2) Difference in QoL-AD score between baseline and follow-up (QoL-Change). Generalized estimating equations were used to analyze longitudinal data, and multinomial …regression analyses were performed. Over the follow-up period the QoL-Baseline model showed greater variability between groups (Wald χ 2  = 172.3, p  < 0.001) than did the QoL-Change model (Wald χ 2  = 1.7, p  = 0.427). In the QoL-Baseline model the predictive factors were greater depression (odds ratio [OR] = 1.20; 95% CI: 1.00– 1.45) and lower functional ability (OR = 0.92; 95% CI: 0.85– 0.99) for the Low QoL group (< 33 QoL-AD), and less depression (OR = 0.68; 95% CI: 0.52– 0.88), more anosognosia (OR = 1.07; 95% CI: 1.01– 1.13), and fewer neuropsychiatric symptoms (OR = 0.95; 95% CI: 0.91– 0.99) for the High-QoL group (>37 QoL-AD). The model based on baseline scores (QoL-Baseline) was better than the QoL-Change model in terms of identifying trajectories and predictors of QoL in AD. Show more

Keywords: Alzheimer’s disease, analytic models, anosognosia, depression, longitudinal study, quality of life

DOI: 10.3233/JAD-160040

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 999-1012, 2016

Authors: Zahodne, Laura B. | Schupf, Nicole | Brickman, Adam M. | Mayeux, Richard | Wall, Melanie M. | Stern, Yaakov | Manly, Jennifer J.

Article Type: Research Article

Abstract: Background: Previous research has identified multiple risk and protective factors for late onset Alzheimer’s disease (LOAD). However, it is not known whether these risk and protective factors differ for individuals who are cognitively stable versus those already experiencing declines. Objective: This study examined how dementia risk factors differ across subgroups of older adults defined by memory trajectory. This line of research may lead to more individualized risk profiles. Methods: Risk factors for incident LOAD were compared across previously-validated groups of older adults exhibiting different memory trajectories (“Stable-High,” “Stable-Low,” “Decliner,” “Rapid Decliner”) using stratified Cox regressions. Participants …included 2,593 racially/ethnically diverse older adults (mean age of 76 at study entry) in the Washington Heights-Inwood Columbia Aging Project. Results: Predictors of incident dementia differed across trajectory groups: older age only incurred independent risk in stable groups, education did not incur independent protection in the rapidly declining group, depression only incurred independent risk in the stable-low group, stroke incurred independent risk in the two extreme groups, and APOE -ɛ 4 only incurred independent risk in the rapidly declining group. Conclusion: The finding that different risk factors for LOAD were associated with specific memory trajectories may reflect the existence of resilience or vulnerability factors that modify the individual influences of risk/protective factors. This study highlights the utility of considering interactions between dementia risk factors and a patient’s unique cognitive history. Show more

Keywords: Aging, Alzheimer’s disease, dementia, memory, neuropsychology

DOI: 10.3233/JAD-151114

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1013-1020, 2016

Authors: Xu, Xin | Hilal, Saima | Collinson, Simon L. | Chan, Qun Lin | Yi Chong, Eddie Jun | Ikram, Mohammad Kamran | Venketasubramanian, Narayanaswamy | Cheng, Ching-Yu | Wong, Tien Yin | Chen, Christopher Li-Hsian

Article Type: Research Article

Abstract: Background: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined. Objective: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample. Methods: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of …total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established. Results: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1–6.4) times higher odds of dementia compared to dementia-free. Discussion: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale. Show more

Keywords: Cerebrovascular disease, cognition, dementia, diagnosis, vascular burden

DOI: 10.3233/JAD-160139

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1021-1028, 2016

Authors: Xing, Yi | Tang, Yi | Zhao, Lina | Wang, Qi | Qin, Wei | Zhang, Jin-Lan | Jia, Jianping

Article Type: Research Article

Abstract: Background: Various evidence demonstrates the influences of ceramides on Alzheimer’s disease (AD) pathogenesis. Furthermore, increased ceramides were also suggested to be related to cognitive decline. However, the association between ceramides and neuropsychiatric symptoms of AD remains unclear. Objective: This study sought to investigate the association between plasma ceramide levels and multiple neuropsychiatric symptoms in AD. Methods: A total of 98 patients and 92 cognitively normal controls participated in this study, including 56 with mild AD and 42 with moderate to severe AD. The Neuropsychiatric Inventory (NPI) was used to assess neuropsychiatric symptoms. Considering the influences …of dementia severity on ceramide levels and neuropsychiatric symptoms, a subgroup analysis was conducted by dementia severity. Results: Except for C24 : 0, all ceramide species were significantly higher in AD patients than in controls. After controlling for confounding factors, the C16 : 0 and C20 : 0 levels were positively associated with delusions, and the quartiles of C22 : 0 and C24 : 0 were positively associated with depression. In the subgroup analysis, association between ceramide species and delusions were only observed in mild AD, and the association between ceramides and depression were prominent in moderate to severe AD. In mild AD, after controlling for age, gender, anti-dementia medications, diabetes status, and ApoE ɛ 4 status, the C16 : 0, C20 : 0, and quartiles of C24 : 1 were associated with delusions. In moderate to severe AD, depression was associated with C22 : 0 and C24 : 0. Conclusion: There were stage-specific associations between ceramides and neuropsychiatric symptoms of AD. The potential mechanisms deserve further investigation. Show more

Keywords: Alzheimer’s disease, ceramides, plasma, psychiatry

DOI: 10.3233/JAD-151158

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1029-1035, 2016

Authors: Hattori, Yorito | Maki, Takakuni | Saito, Satoshi | Yamamoto, Yumi | Nagatsuka, Kazuyuki | Ihara, Masafumi

Article Type: Research Article

Abstract: Accumulation of amyloid-β peptide (Aβ) in the brain is one of the most important features of Alzheimer’s dementia (AD). Cerebral amyloid angiopathy (CAA) is characterized by Aβ accumulation in the walls of cerebral arteries and capillaries, and is present in over 90% of patients with AD. Several novel agents for AD/CAA developed around the amyloid hypothesis have shown positive signs in animal studies but have failed in clinical trials due to adverse events and/or lack of efficiency. As CAA is presumably caused by a failure in Aβ clearance, drugs that promote Aβ clearance may hold promise in the treatment of …CAA and possibly AD. With this in mind, cilostazol, an anti-platelet drug with vasodilating action, has been found to promote Aβ clearance along perivascular drainage pathway, reduce Aβ accumulation in the brain, and restore memory impairment in Tg-SwDI mice, an animal model of CAA. We therefore tested whether the most common anti-platelet agent, aspirin, also reduced Aβ and rescued cognitive impairment in Tg-SwDI mice, and also whether aspirin affected hemorrhagic complications that can occur in Tg-SwDI mice. Mice aged 4 months were assigned into vehicle-treated and low-dose aspirin-treated groups. Low-dose aspirin for 8 months did not increase hemorrhagic lesions, nor increase resting cerebral blood flow or cerebral vascular reserve in response to hypercapnia or acetylcholine. Subsequently, aspirin did not restore cognitive dysfunction. These results suggest that low-dose aspirin does not have a direct influence on cerebrovascular Aβ metabolism nor aggravate hemorrhagic complications in CAA. Show more

Keywords: Alzheimer’s dementia, amyloid β, aspirin, cerebral amyloid angiopathy

DOI: 10.3233/JAD-160013

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1037-1045, 2016

Authors: Nilsson, Erik D. | Melander, Olle | Elmståhl, Sölve | Lethagen, Eva | Minthon, Lennart | Pihlsgård, Mats | Nägga, Katarina

Article Type: Research Article

Abstract: Background: Copeptin is a reliable surrogate marker for the neurohypophyseal hormone vasopressin. Elevated plasma level of copeptin has been associated with cardiovascular and metabolic disease risk. Objective: To investigate the association between copeptin and risk of dementia. Methods: In all, 18,240 individuals from Malmö, Sweden, were examined between 2002 and 2006 (mean age 69.3 years, 69.8% men). Incident cases of dementia until 31 December 2009 were identified by linkage with the Swedish National Patient Register. To validate the dementia diagnoses, medical records as well as laboratory and neuroimaging data were carefully reviewed. Baseline level of …copeptin was measured in frozen plasma in: (1) all participants who were diagnosed with dementia during follow-up, (2) a random sample of 5100 individuals of the cohort. Results: During a median follow-up of 4.2 years, there were 374 incident dementia cases (age range 60–83 years at baseline): 120 were classified as Alzheimer’s disease (AD), 84 as vascular dementia (VaD), and 102 as mixed dementia. In logistic regressions adjusted for cardiovascular risk factors, baseline level of copeptin predicted incident VaD (Odds ratio (OR) 1.30 per 1 SD increase in log copeptin, 95% CI 1.03–1.64). Copeptin did not predict incidence of all-cause dementia (OR 1.05, 95% CI 0.94–1.18), AD (OR 0.97, 95% CI 0.79–1.18), or mixed dementia (OR 0.85, 95% CI 0.68–1.05). Conclusion: Elevated plasma level of copeptin is a risk marker for incident VaD, but not for incident AD. This suggests that the vasopressin hormonal system might be involved in the development of VaD. Show more

Keywords: Alzheimer’s disease, copeptin, dementia, vascular dementia

DOI: 10.3233/JAD-151118

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1047-1053, 2016

Authors: Ingber, Adam P. | Hassenstab, Jason | Fagan, Anne M. | Benzinger, Tammie L.S. | Grant, Elizabeth A. | Holtzman, David M. | Morris, John C. | Roe, Catherine M.

Article Type: Research Article

Abstract: Background: The influence of reserve variables and Alzheimer’s disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on “non-cognitive” outcomes, including functional abilities and mood. Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were …cognitively normal at baseline (Clinical Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive reserve, dementia

DOI: 10.3233/JAD-150478

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1055-1064, 2016

Authors: Henneges, Carsten | Reed, Catherine | Chen, Yun-Fei | Dell’Agnello, Grazia | Lebrec, Jeremie

Article Type: Research Article

Abstract: Background: Improved understanding of the pattern of cognitive decline in Alzheimer’s disease (AD) would be useful to assist primary care physicians in explaining AD progression to patients and caregivers. Objective: To identify the sequence in which cognitive abilities decline in community-dwelling patients with AD. Methods: Baseline data were analyzed from 1,495 patients diagnosed with probable AD and a Mini-Mental State Examination (MMSE) score ≤ 26 enrolled in the 18-month observational GERAS study. Proportional odds logistic regression models were applied to model MMSE subscores (orientation, registration, attention and concentration, recall, language, and drawing) and the corresponding …subscores of the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog), using MMSE total score as the index of disease progression. Probabilities of impairment start and full impairment were estimated at each MMSE total score level. Results: From the estimated probabilities for each MMSE subscore as a function of the MMSE total score, the first aspect of cognition to start being impaired was recall, followed by orientation in time, attention and concentration, orientation in place, language, drawing, and registration. For full impairment in subscores, the sequence was recall, drawing, attention and concentration, orientation in time, orientation in place, registration, and language. The sequence of cognitive decline for the corresponding ADAS-cog subscores was remarkably consistent with this pattern. Conclusion: The sequence of cognitive decline in AD can be visualized in an animation using probability estimates for key aspects of cognition. This might be useful for clinicians to set expectations on disease progression for patients and caregivers. Show more

Keywords: Alzheimer’s disease, cognition, disease progression, observational study

DOI: 10.3233/JAD-150852

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1065-1080, 2016

Authors: Liu, Cheng-Hui | Bu, Xian-Le | Wang, Jun | Zhang, Tao | Xiang, Yang | Shen, Lin-Lin | Wang, Qing-Hua | Deng, Bo | Wang, Xin | Zhu, Chi | Yao, Xiu-Qing | Zhang, Meng | Zhou, Hua-Dong | Wang, Yan-Jiang

Article Type: Research Article

Abstract: Background: Capsaicin-rich diets are common worldwide. Capsaicin has been shown to have favorable effects on various diseases including atherosclerosis, cardiovascular diseases, stroke, obesity, hypertension, cancer, and gastrointestinal and inflammatory diseases. The impact of capsaicin on Alzheimer’s disease (AD), which is the most common form of dementia in the elderly, remains unknown. Objective: To investigate the correlations of capsaicin intake with cognition and blood markers of AD. Methods: A total of 338 participants aged 40 years or older were enrolled from communities. Dietary habits regarding chili pepper consumption were collected using a Food Frequency Questionnaire (FFQ). …Cognitive function was measured using the Chinese version of the Mini-Mental State Examination (MMSE). Blood amyloid-β (Aβ)40 and Aβ42 were measured with ELISA kits. Results: In univariate analysis, MMSE scores (r  = 0.209, p  < 0.001), serum Aβ40 levels (r  = –0.149, p  = 0.006), the ratio of Aβ42 /Aβ40 (r  = 0.11, p  = 0.043) and total serum Aβ levels (r  = –0.097, p  = 0.075), but not serum Aβ42 levels (r  = 0.17, p  = 0.757), were significantly correlated with total capsaicin diet scores. In multivariate analysis, total capsaicin diet scores were positively associated with MMSE scores and inversely associated with serum Aβ40 levels, and total serum Aβ levels, but not serum Aβ42 levels and the ratio of Aβ42 /Aβ40 , after adjustment for age, gender, educational level, smoking history, alcohol consumption, body mass index (BMI) and comorbidities. Conclusion: These findings suggest that a capsaicin-rich diet may exert favorable effects on AD blood biomarkers and cognitive function in middle-aged and elderly adults. Show more

Keywords: Alzheimer’s disease, amyloid-beta, capsaicin, cognitive function

DOI: 10.3233/JAD-151079

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1081-1088, 2016

Authors: Wang, Wei | Lu, Lu | Wu, Qiao-qi | Jia, Jian-ping

Article Type: Research Article

Abstract: Amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, and neuroinflammation are major pathophysiological events in Alzheimer’s disease (AD). However, the relationships among these processes and which first exerts an effect are unknown. In the present study, we investigated age-dependent behavioral changes and the sequential pathological progression from the brain to the periphery in AD transgenic (PS1V97L -Tg) mice and their wild-type littermates. We discovered that the brain Aβ significantly increased at 6 months old, the increased brain Aβ caused memory dysfunction, and the ability of Aβ to induce tau hyperphosphorylation might be due to oxidative stress and neuroinflammatory reactions. The levels …of Aβ42 , total tau (t-tau), oxidative stress parameters, and proinflammatory cytokines in plasma can be used to differentiate between PS1V97L -Tg mice and their wild-type littermates at different time points. Collectively, our findings support the hypothesis that Aβ is a trigger among these pathophysiological processions and show that plasma biomarkers can reflect the condition of the AD brain. Show more

Keywords: Alzheimer’s disease, amyloid-β, oxidative stress, proinflammatory cytokines, PS1V97L-Tg mouse, tau

DOI: 10.3233/JAD-160004

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1089-1099, 2016

Authors: Kim, Hee-Jin | Im, Hyung Kyun | Kim, Juhan | Han, Jee-young | de Leon, Mony | Deshpande, Anup | Moon, Won-Jin

Article Type: Research Article

Abstract: Background: Rapid eye movement sleep behavior disorder (RBD) may present as an early manifestation of an evolving neurodegenerative disorder with alpha-synucleinopathy. Objective: We investigated that dementia with RBD might show distinctive cortical atrophic patterns. Methods: A total of 31 patients with idiopathic Parkinson’s disease (IPD), 23 with clinically probable Alzheimer’s disease (AD), and 36 healthy controls participated in this study. Patients with AD and IPD were divided into two groups according to results of polysomnography and rated with a validated Korean version of the RBD screening questionnaire (RBDSQ-K), which covers the clinical features of RBD. …Voxel-based morphometry was adapted for detection of regional brain atrophy among groups of subjects. Results: Scores on RBDSQ-K were higher in the IPD group (3.54 ± 2.8) than in any other group (AD, 2.94 ± 2.4; healthy controls, 2.31 ± 1.9). Atrophic changes according to RBDSQ-K scores were characteristically in the posterior part of the brain and brain stem, including the hypothalamus and posterior temporal region including the hippocampus and bilateral occipital lobe. AD patients with RBD showed more specialized atrophic patterns distributed in the posterior and inferior parts of the brain including the bilateral temporal and occipital cortices compared to groups without RBD. The IPD group with RBD showed right temporal cortical atrophic changes. Conclusion: The group of patients with neurodegenerative diseases and RBD showed distinctive brain atrophy patterns, especially in the posterior and inferior cortices. These results suggest that patients diagnosed with clinically probable AD or IPD might have mixed pathologies including α -synucleinopathy. Show more

Keywords: Brain atrophy, dementia, RBD screening questionnaire, REM sleep disorder, voxel-based morphometry

DOI: 10.3233/JAD-151197

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1101-1109, 2016

Authors: Mulder, Cornelis K. | Dong, Yun | Brugghe, Humphrey F. | Timmermans, Hans A.M. | Tilstra, Wichard | Westdijk, Janny | van Riet, Elly | van Steeg, Harry | Hoogerhout, Peter | Eisel, Ulrich L.M.

Article Type: Research Article

Abstract: Background: Soluble oligomeric (misfolded) species of amyloid-β (Aβ) are the main mediators of toxicity in Alzheimer’s disease (AD). These oligomers subsequently form aggregates of insoluble fibrils that precipitate as extracellular and perivascular plaques in the brain. Active immunization against Aβ is a promising disease modifying strategy. However, eliciting an immune response against Aβ in general may interfere with its biological function and was shown to cause unwanted side-effects. Therefore, we have developed a novel experimental vaccine based on conformational neo-epitopes that are exposed in the misfolded oligomeric Aβ, inducing a specific antibody response. Objective: Here we investigate …the protective effects of the experimental vaccine against oligomeric Aβ1-42 -induced neuronal fiber loss in vivo . Methods: C57BL/6 mice were immunized or mock-immunized. Antibody responses were measured by enzyme-linked immunosorbent assay. Next, mice received a stereotactic injection of oligomeric Aβ1-42 into the nucleus basalis of Meynert (NBM) on one side of the brain (lesion side), and scrambled Aβ1-42 peptide in the contralateral NBM (control side). The densities of choline acetyltransferase-stained cholinergic fibers origination from the NBM were measured in the parietal neocortex postmortem. The percentage of fiber loss in the lesion side was determined relative to the control side of the brain. Results: Immunized responders (79%) showed 23% less cholinergic fiber loss (p  = 0.01) relative to mock-immunized mice. Moreover, fiber loss in immunized responders correlated negatively with the measured antibody responses (R2  = 0.29, p  = 0.02). Conclusion: These results may provide a lead towards a (prophylactic) vaccine to prevent or at least attenuate (early onset) AD symptoms. Show more

Keywords: Alzheimer’s disease, amyloid-β protein (1–42), cholinergic fibers, cyclopeptides, immunization, mice, nucleus basalis of Meynert, stereotactic injection

DOI: 10.3233/JAD-151136

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1111-1123, 2016

Authors: Cretin, Benjamin | Sellal, François | Philippi, Nathalie | Bousiges, Olivier | Di Bitonto, Laure | Martin-Hunyadi, Catherine | Blanc, Frederic

Article Type: Research Article

Abstract: Background: Aside from rare case reports, only one study, with 12 patients, has addressed the phenotypic presentation of epilepsy in clinically defined amnestic mild cognitive impairment (aMCI, presumed to correspond to the AD prodromal stage): the authors highlighted a pharmacosensitive non-convulsive partial epileptic syndrome most probably related to the temporal or temporo-frontal cortices. Objective: The objective of this study was to verify the existence and the syndromic features of epileptic prodromal AD in a tertiary Memory Clinic. Methods: We conducted a retrospective, single-center study of the electro-radio-clinical features of 13 cases of epileptic prodromal AD …patients (3.1% of a cohort of MCI, n  = 430 subjects), selected on both clinical criteria and CSF biomarkers. Results: In our patients, a pharmacosensitive temporal lobe epilepsy syndrome, inaugurating prodromal AD, started at a mean age of 63 years (±12.8 years) and preceded MCI diagnosis by 4 to 7 years. At the stage of aMCI, median MMSE score was 26 and imaging showed mild hippocampal atrophy. After almost one year under treatment, cognitive complaints were not relieved but the MMSE score remained stable at 26 for 11 patients (2 patients were excluded from analysis because of the onset of aphasic or neurovisual symptoms altering MMSE scoring). Conclusion: Our data, in conjunction with those of the 12 previously described subjects, suggest the existence of a currently unrecognized inaugural epilepsy syndrome of sporadic AD. Such a syndrome could be called the epileptic variant of AD because seizures are its sole feature for more than 2.5 years. Show more

Keywords: Alzheimer’s disease, mild cognitive impairment, partial seizures, temporal lobe epilepsy

DOI: 10.3233/JAD-150096

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1125-1133, 2016

Authors: Meng, Xiangbao | Luo, Yun | Liang, Tian | Wang, Mengxia | Zhao, Jingyu | Sun, Guibo | Sun, Xiaobo

Article Type: Research Article

Abstract: A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer’s disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng , ameliorated amyloid-β (Aβ)25-35 -induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, …which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40 , and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40 , and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer’s disease by activating TFEB. Show more

Keywords: APP/PS1 mice, autophagy flux, lysosome biogenesis, transcription factor EB

DOI: 10.3233/JAD-160096

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1135-1150, 2016

Article Type: Other

DOI: 10.3233/JAD-160313

Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1151-1155, 2016