Journal of Alzheimer's Disease - Volume 58, issue 2

Authors: Viaña, John Noel M. | Bittlinger, Merlin | Gilbert, Frederic

Article Type: Review Article

Abstract: Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer’s disease, with several recruiting participants <65 and thus have early-onset Alzheimer’s disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes …that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies. Show more

Keywords: Clinical trials as topic, deep brain stimulation, early onset Alzheimer’s disease, ethical review, ethics, familial Alzheimer’s disease, fornix (brain), nucleus basalis of Meynert

DOI: 10.3233/JAD-161073

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 289-301, 2017

Authors: Yuan, Xiang-Zhen | Sun, Sen | Tan, Chen-Chen | Yu, Jin-Tai | Tan, Lan

Article Type: Review Article

Abstract: As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer’s disease (AD) both in vitro and in vivo . However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aβ but may also affect the …pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AβPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD. Show more

Keywords: ADAM10, Alzheimer’s disease, amyloid-β, amyloid protein, biomarker, gliogenesis, neurogenesis, tau protein

DOI: 10.3233/JAD-170061

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 303-322, 2017

Authors: Paolacci, Lucia | Giannandrea, David | Mecocci, Patrizia | Parnetti, Lucilla

Article Type: Review Article

Abstract: In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer’s disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of …the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors ), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the “fit” subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group. Show more

Keywords: Aging, Alzheimer’s disease, biomarker, cerebrospinal fluid, MRI, oldest-old, PET

DOI: 10.3233/JAD-161127

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 323-335, 2017

Authors: Harding, Alice | Robinson, Sarita | Crean, StJohn | Singhrao, Sim K.

Article Type: Research Article

Abstract: A risk factor relationship exists between periodontal disease and Alzheimer’s disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis , to gain greater virulence. The initial process involves …P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-β, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia. Show more

Keywords: Alzheimer’s disease, manageable risk factor, memory, P. gingivalis, periodontitis, sleep

DOI: 10.3233/JAD-170046

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 337-348, 2017

Authors: Yamazaki, Chiemi | Tamaoki, Toshio | Nunomura, Akihiko | Tamai, Kenichi | Yasuda, Kazuyuki | Motohashi, Nobutaka

Article Type: Short Communication

Abstract: To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer’s disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40 , but not Aβ42 nor Aβ40 /Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects …of ECT against amyloid dysmetabolism. Show more

Keywords: Alzheimer’s disease, amyloid-β, electroconvulsive therapy, late-life depression, mild cognitive impairment, neuroimaging, parahippocampal atrophy, plasma biomarker

DOI: 10.3233/JAD-170111

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 349-354, 2017

Authors: Yilmaz, Ali | Geddes, Tim | Han, BeomSoo | Bahado-Singh, Ray O. | Wilson, George D. | Imam, Khaled | Maddens, Michael | Graham, Stewart F.

Article Type: Short Communication

Abstract: Using 1 H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (n  = 12), mild cognitive impairment (MCI) sufferers (n  = 8), and Alzheimer’s disease (AD) patients (n  = 9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls. This pilot study demonstrates the potential for using metabolomics and saliva for the early diagnosis of AD. Given the ease and convenience of collecting saliva, the development of accurate and sensitive salivary biomarkers would be ideal for screening those at greatest risk of developing AD.

Keywords: Alzheimer’s disease, 1H NMR, metabolomics, mild cognitive impairment

DOI: 10.3233/JAD-161226

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 355-359, 2017

Authors: Li, Kan | Chan, Wenyaw | Doody, Rachelle S. | Quinn, Joseph | Luo, Sheng | the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Identifying predictors of conversion to Alzheimer’s disease (AD) is critically important for AD prevention and targeted treatment. Objective: To compare various clinical and biomarker trajectories for tracking progression and predicting conversion from amnestic mild cognitive impairment to probable AD. Methods: Participants were from the ADNI-1 study. We assessed the ability of 33 longitudinal biomarkers to predict time to AD conversion, accounting for demographic and genetic factors. We used joint modelling of longitudinal and survival data to examine the association between changes of measures and disease progression. We also employed time-dependent receiver operating characteristic method …to assess the discriminating capability of the measures. Results: 23 of 33 longitudinal clinical and imaging measures are significant predictors of AD conversion beyond demographic and genetic factors. The strong phenotypic and biological predictors are in the cognitive domain (ADAS-Cog; RAVLT), functional domain (FAQ), and neuroimaging domain (middle temporal gyrus and hippocampal volume). The strongest predictor is ADAS-Cog 13 with an increase of one SD in ADAS-Cog 13 increased the risk of AD conversion by 2.92 times. Conclusion: Prediction of AD conversion can be improved by incorporating longitudinal change information, in addition to baseline characteristics. Cognitive measures are consistently significant and generally stronger predictors than imaging measures. Show more

Keywords: ADNI, joint modeling, longitudinal and survival data, mild cognitive impairment, prediction

DOI: 10.3233/JAD-161201

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 361-371, 2017

Authors: Mirheidari, Bahman | Blackburn, Daniel | Harkness, Kirsty | Walker, Traci | Venneri, Annalena | Reuber, Markus | Christensen, Heidi

Article Type: Research Article

Abstract: Background: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD). Objective: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated. Methods: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a …specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD. Results: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier.Using only the ten best features, the mean correct classification score increased to 95%. Conclusion: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD. Show more

Keywords: analysis, dementia, language, machine learning, speech recognition software

DOI: 10.3233/JAD-160507

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 373-387, 2017

Authors: Segal-Gavish, Hadar | Danino, Ortal | Barhum, Yael | Ben-Zur, Tali | Shai, Ella | Varon, David | Offen, Daniel | Fischer, Bilha

Article Type: Research Article

Abstract: Background: Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer’s disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5’-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2 O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant. Objective: To further explore SAS ability to protect the brain from Aβ toxicity …both in vitro and in vivo . Methods: We evaluated SAS ability to decompose or inhibit the formation of Aβ42 -M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD. Results: We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42 -Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months. Conclusion: Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model. Show more

Keywords: P2Y receptors, nucleotides, amyloid-β aggregates, metal-ion chelation, neuroprotection, 5XFAD mouse model, behavioral disinhibition, spatial working memory

DOI: 10.3233/JAD-161236

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 389-400, 2017

Authors: Rafii, Michael S. | Skotko, Brian G. | McDonough, Mary Ellen | Pulsifer, Margaret | Evans, Casey | Doran, Eric | Muranevici, Gabriela | Kesslak, Patrick | Abushakra, Susan | Lott, Ira T. | for the ELND005-DS Study Group

Article Type: Research Article

Abstract: Background: ELND005 (scyllo -Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who …met study eligibility criteria were randomly assigned in a 2 : 1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy. Show more

Keywords: Alzheimer’s disease, amyloid, dementia, Down syndrome, Myo-inositol

DOI: 10.3233/JAD-160965

Citation: Journal of Alzheimer's Disease, vol. 58, no. 2, pp. 401-411, 2017