Journal of Alzheimer's Disease - Volume 56, issue 2

Authors: Siegel, Andrew M. | Barrett, Marna S. | Bhati, Mahendra T.

Article Type: Review Article

Abstract: Deep brain stimulation (DBS) is an invasive neuromodulation modality that has shown early promise as a novel treatment of Alzheimer’s disease (AD). Further clinical research is warranted on the basis of positive results from animal and human studies, as well as the inadequacy of existing treatments in reducing the enormous medical and financial costs of untreated AD. Nevertheless, unique ethical challenges require particular attention to elements of subject enrollment and informed consent. Study protocols should specify robust assessment and regular monitoring of subject decision-making capacity to consent to trial participation. Investigators should also assess for and mitigate therapeutic misconception (the …phenomenon whereby a research participant conflates the goals of research with those of clinical treatment) and ensure that all prospective trial participants have adequate post-trial access to treatment and DBS device maintenance. In the following discussion, each issue is summarized and followed by recommendations for proper ethical procedure. We conclude by assimilating relevant ethical considerations into a decision-making algorithm designed to aid future clinical investigators of DBS for AD with the task of ethical subject enrollment. Show more

Keywords: Advance directive, Alzheimer’s disease, deep brain stimulation, informed consent, research ethics

DOI: 10.3233/JAD-160356

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 429-439, 2017

Authors: Sabbagh, Marwan N. | Schäuble, Barbara | Anand, Keshav | Richards, Danielle | Murayama, Shigeo | Akatsu, Hiroyasu | Takao, Masaki | Rowe, Christopher C. | Masters, Colin L. | Barthel, Henryk | Gertz, Hermann-Josef | Peters, Oliver | Rasgon, Natalie | Jovalekic, Aleksandar | Sabri, Osama | Schulz-Schaeffer, Walter J. | Seibyl, John

Article Type: Short Communication

Abstract: Of 57 individuals diagnosed with Alzheimer’s disease (AD) in a phase III study, 13 (23%) had amyloid-β (Aβ) levels on postmortem histopathology that did not explain the dementia. Based on postmortem histopathology, a wide range of different non-AD conditions was identified, including frontotemporal dementia, hippocampal sclerosis, and dementia with Lewy bodies. Of the histopathologically Aβ negative scored cases ante-mortem Florbetaben PET scans were classified as negative for Aβ in 11 patients based on visual analysis and in all 12 quantifiable cases based on composite standardized uptake value ratios. Thus, florbetaben PET can assist physicians in the differential diagnosis of neurodegenerative …disorders by reliably excluding Aβ pathology. Show more

Keywords: Alzheimer’s disease, florbetaben PET, histopathology

DOI: 10.3233/JAD-160821

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 441-446, 2017

Authors: Hird, Megan A. | Vesely, Kristin A. | Fischer, Corinne E. | Graham, Simon J. | Naglie, Gary | Schweizer, Tom A.

Article Type: Short Communication

Abstract: The areas of driving impairment characteristic of mild cognitive impairment (MCI) remain unclear. This study compared the simulated driving performance of 24 individuals with MCI, including amnestic single-domain (sd-MCI, n  = 11) and amnestic multiple-domain MCI (md-MCI, n  = 13), and 20 age-matched controls. Individuals with MCI committed over twice as many driving errors (20.0 versus 9.9), demonstrated difficulty with lane maintenance, and committed more errors during left turns with traffic compared to healthy controls. Specifically, individuals with md-MCI demonstrated greater driving difficulty compared to healthy controls, relative to those with sd-MCI. Differentiating between different subtypes of MCI may be important when …evaluating driving safety. Show more

Keywords: Automobile driving, cognition, computer simulation patient outcome assessment, mild cognitive impairment

DOI: 10.3233/JAD-160995

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 447-452, 2017

Authors: Imtiaz, Bushra | Tolppanen, Anna Maija | Solomon, Alina | Soininen, Hilkka | Kivipelto, Miia

Article Type: Short Communication

Abstract: Cardiovascular Risk factors, Aging and Dementia (CAIDE) is a Finnish population-based study. 731 cognitively normal women had self-reported hormone therapy (HT) data in 1998 as: no use, use ≤5 years, and >5 years. Information on type of HT was only available from 1995–1998 (Prescription Register). Cognition was assessed in 1998 and 2005–2008. Long-term (>5 years) HT use, especially use of estradiol alone among women having hysterectomy with bilateral oophorectomy, was associated with better episodic memory in 1998, but not in 2005–2008. Although a strong evidence for protective effect of estradiol on cognition was not observed in our study, improved global …cognition among long-term users suggests that long-term postmenopausal HT may be beneficial for some cognitive domains. Show more

Keywords: Cognition, dementia, estradiol, hormone therapy, menopause

DOI: 10.3233/JAD-160643

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 453-458, 2017

Authors: Doran, Eric | Keator, David | Head, Elizabeth | Phelan, Michael J. | Kim, Ron | Totoiu, Minodora | Barrio, Jorge R. | Small, Gary W. | Potkin, Steven G. | Lott, Ira T.

Article Type: Research Article

Abstract: Overexpression of the amyloid precursor protein (APP) gene on chromosome 21 in Down syndrome (DS) has been linked to increased brain amyloid levels and early-onset Alzheimer’s disease (AD). An elderly man with phenotypic DS and partial trisomy of chromosome 21 (PT21) lacked triplication of APP affording an opportunity to study the role of this gene in the pathogenesis of dementia. Multidisciplinary studies between ages 66–72 years comprised neuropsychological testing, independent neurological exams, amyloid PET imaging with 11 C-Pittsburgh compound-B (PiB), plasma amyloid-β (Aβ) measurements, and a brain autopsy examination. The clinical phenotype was typical for DS and his intellectual disability …was mild in severity. His serial neuropsychological test scores showed less than a 3% decline as compared to high functioning individuals with DS who developed dementia wherein the scores declined 17–28% per year. No dementia was detected on neurological examinations. On PiB-PET scans, the patient with PT21 had lower PiB standard uptake values than controls with typical DS or sporadic AD. Plasma Aβ42 was lower than values for demented or non-demented adults with DS. Neuropathological findings showed only a single neuritic plaque and neurofibrillary degeneration consistent with normal aging but not AD. Taken together the findings in this rare patient with PT21 confirm the obligatory role of APP in the clinical, biochemical, and neuropathological findings of AD in DS. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid β-protein precursor, APP, dementia, down syndrome, partial trisomy 21, PiB-PET, trisomy 21

DOI: 10.3233/JAD-160836

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 459-470, 2017

Authors: Chen, Jing | Zhan, Libin | Lu, Xiaoguang | Xiao, Chi | Sun, Nijing

Article Type: Research Article

Abstract: Diabetes-associated cognitive decline (DACD) is a brain injury induced by diabetes mellitus, with cognitive impairment as the major symptom. Growing evidence has revealed that DACD is correlated with disruptions in synapses involved in cognition. Within synapses, more specifically in areas of postsynaptic density (PSD), there is a high concentration of proteins that receive and transduce synaptic information. In the present study, to identify the differentially expressed PSD proteins among DACD mice, ZiBuPiYin recipe (ZBPYR)-treated DACD mice and control mice, we applied isobaric tags for relative and absolute quantitation (iTRAQ) with LC-MS/MS technology, by which three biological replicates and three technical …replicates were examined. A total of 24 and 23 differentially expressed proteins were observed in control versus DACD mice and in DACD versus ZBPYR-treated DACD mice, respectively. Notably, we found ‘Protein processing in endoplasmic reticulum’ and ‘PI3K-Akt signaling pathway’ might be impaired in DACD pathogenesis, while Growth factor receptor-bound protein 2 might be a crucial protein as a molecular target of the neuroprotective effects of ZBPYR. To our knowledge, this is the first study to provide a reference proteome map for DACD and ZBPYR-treated DACD mouse forebrain PSD to aid understanding the underlying mechanisms of DACD and ZBPYR. Show more

Keywords: Cognitive impairments, diabetes-related complications, post-synaptic density, proteome, traditional Chinese medicine

DOI: 10.3233/JAD-160691

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 471-489, 2017

Authors: Su, Fan | Shu, Hao | Ye, Qing | Xie, Chunming | Yuan, Baoyu | Zhang, Zhijun | Bai, Feng

Article Type: Research Article

Abstract: The aim of the study was to investigate the cognitive significance of the changes in default mode network (DMN) during the process of Alzheimer’s disease (AD) and the genetic basis that drives the alteration. Eighty-seven subjects with mild cognitive impairment (MCI) and 131 healthy controls (HC) were employed at baseline, and they had the genetic risk scores (GRS) based on the GWAS-validated AD-related top loci. Eleven MCIs who converted to AD (c-MCIs), 32 subjects who remained stable (nc-MCIs), and 56 HCs participated in the follow-up analyses after an average of 35 months. Decreased functional connectivity (FC) within temporal cortex was …identified for MCIs at baseline, which was partially determined by the GRS; moreover, compensations may occur within the frontal-parietal brain to maintain relatively intact cognition. During the follow-ups, c-MCIs exhibited more FC declines within the prefrontal-parietal lobes and parahippocampal gyrus/hippocampus than the HCs and nc-MCIs. The GRS did not significantly vary among the three groups, whereas associations were identified at risky alleles and FC declines in all AD spectra. Interestingly, the influence of APOE ɛ 4 varied as the disease progressed; APOE ɛ 4 was associated with longitudinal FC decreases only for HCs in the single variance-based analyses and deteriorated DMN integration in nc-MCIs by combining the effects of other loci. However, the GRS without APOE ɛ 4 predicted FC decline for converters. It is suggested that the integration of multilocus genetic risk predicted the longitudinal trajectory of DMN and may be used as a clinical strategy to track AD progression. Show more

Keywords: Alzheimer’s disease, default mode network, functional MRI, genetic polymorphism, longitudinal investigation, mild cognitive impairment

DOI: 10.3233/JAD-160787

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 491-507, 2017

Authors: Pimouguet, Clément | Le Goff, Mélanie | Wittwer, Jérôme | Dartigues, Jean-François | Helmer, Catherine

Article Type: Research Article

Abstract: Background: There is a growing interest in developing non-pharmacological approaches in dementia. Clinical efficacy of occupational therapy (OT) under routine care conditions has not been investigated yet. Objective: To analyze the short-term effects of OT in patients with dementia; and to identify factors related to greater benefit. Methods: Patients referred to OT were evaluated before starting a 3-month intervention and at 3 and 6 months later. Measures included: Mini-Mental State Examination (MMSE), Disability Assessment in Dementia (DAD), Neuropsychiatric Inventory (NPI) Questionnaire, patients’ quality of life (EQ 5D-VAS), caregivers’ burden (Zarit scale), and amount of informal …care. Linear mixed models were used to analyze trajectories of outcomes. Logistic regressions with stepwise descending selection were used to study factors associated with benefits. Results: 421 dementia patients benefited from OT (mean MMSE = 17.3). Patients remained cognitively stable over time. Functional performances also remained stable at 3 months and significantly decreased at 6 months (crude reduction of 2.8 points, p  < 0.01). Behavioral troubles were significantly reduced over the intervention period and remained stable after (p  < 0.01). Patients’ quality of life increased over the 3-month intervention (p  = 0.16) and significantly decreased thereafter. Caregivers’ burden and informal care significantly decreased over the 3-month intervention and remained stable thereafter. Patients who benefited from OT with regard to function were less educated and had higher cognitive level. Conclusion: OT may be an effective intervention to maintain cognition and functionality and to reduce psychiatric symptoms in dementia patients. Mild stages of dementia could gain more benefits from OT with regard to functional decline. Show more

Keywords: Behavioral troubles, cognition, dementia, function, non-pharmacological intervention, observation study, occupational therapy

DOI: 10.3233/JAD-160820

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 509-517, 2017

Authors: Monacelli, Fiammetta | Signori, Alessio | Roffredo, Laura | Pace, Katiuscia | Nencioni, Alessio | Pickering, Gisele | Nicolas, Macian | Odetti, Patrizio

Article Type: Research Article

Abstract: Pain is still a neglected clinical issue in elderly people with dementia and/or communicative disorders, with an unacceptable higher rate of under diagnosis and under treatment. Cognitive deficit and emotional and psychological disturbances entangle pain symptoms, affecting patient self-report. So far, observational pain tools do not have fully adequate clinimetric properties and quality requirements for easy-to-use daily rating. Older patients with dementia represent a clinical challenge. The assessment of pain is important for improving clinical outcomes, such as functional status, frailty trajectories, comorbidity, and quality of life. The PAINAID scale appears to be the most accurate pain tool in people …with dementia along with the Algoplus® scale, a recently developed tool to rapidly assess acute pain in hospitals settings. The present study aimed to assess the clinimetric properties of the Algoplus® , as compared to PAINAID, for detecting acute pain in a real-world cohort of hospitalized older patients with dementia. Show more

Keywords: Algoplus® scale, aged, dementia, pain

DOI: 10.3233/JAD-160790

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 519-527, 2017

Authors: Kotani, Rina | Urano, Yasuomi | Sugimoto, Hachiro | Noguchi, Noriko

Article Type: Research Article

Abstract: The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer’s disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ -secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in …human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ -secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, curcumin derivatives, endoplasmic reticulum

DOI: 10.3233/JAD-160794

Citation: Journal of Alzheimer's Disease, vol. 56, no. 2, pp. 529-542, 2017