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

Authors: Pretorius, Etheresia | Bester, Janette | Kell, Douglas B.

Article Type: Review Article

Abstract: The progression of Alzheimer’s disease (AD) is accompanied by a great many observable changes, both molecular and physiological. These include oxidative stress, neuroinflammation, and (more proximal to cognitive decline) the death of neuronal and other cells. A systems biology approach seeks to organize these observed variables into pathways that discriminate those that are highly involved (i.e., causative) from those that are more usefully recognized as bystander effects. We review the evidence that iron dysregulation is one of the central causative pathway elements here, as this can cause each of the above effects. In addition, we review the evidence that dormant, …non-growing bacteria are a crucial feature of AD, that their growth in vivo is normally limited by a lack of free iron, and that it is this iron dysregulation that is an important factor in their resuscitation. Indeed, bacterial cells can be observed by ultrastructural microscopy in the blood of AD patients. A consequence of this is that the growing cells can shed highly inflammatory components such as lipopolysaccharides (LPS). These too are known to be able to induce (apoptotic and pyroptotic) neuronal cell death. There is also evidence that these systems interact with elements of vitamin D metabolism. This integrative systems approach has strong predictive power, indicating (as has indeed been shown) that both natural and pharmaceutical iron chelators might have useful protective roles in arresting cognitive decline, and that a further assessment of the role of microbes in AD development is more than highly warranted. Show more

Keywords: Alzheimer’s disease, bacteria, dormancy, dysbiosis, eryptosis, iron, LPS, systems biology, ultramicroscopy

DOI: 10.3233/JAD-160318

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1237-1256, 2016

Authors: Adiele, Reginald C. | Adiele, Chiedukam A.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an age-associated neurodegenerative brain disorder with progressive cognitive decline that leads to terminal dementia and death. For decades, amyloid-beta (Aβ) and neurofibrillary tangle (NFT) aggregation hypotheses have dominated studies on the pathogenesis and identification of potential therapeutic targets in AD. Little attention has been paid to the mitochondrial molecular/biochemical pathways leading to AD. Mitochondria play a critical role in cell viability and death including neurons and neuroglia, not only because they regulate energy and oxygen metabolism but also because they regulate cell death pathways. Mitochondrial impairment and oxidative stress are implicated in the pathogenesis of AD. …Interestingly, current therapeutics provide symptomatic benefits to AD patients resulting in the use of preventive trials on presymptomatic subjects. This review article elucidates the pathophysiology of AD and emphasizes the need to explore the mitochondrial pathways to provide solutions to unanswered questions in the prevention and treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid-beta, mitochondria, neurofibrillary tangles, neuronal death, oxidative stress

DOI: 10.3233/JAD-150967

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1257-1270, 2016

Authors: Allen, Herbert B.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is an infectious disease caused by spirochetes, and these spirochetes form biofilms, which attract the innate immune system. The innate immune system first responder, Toll-like receptor 2, generates both NF-κ B and TNF-α which try to kill the spirochetes in the biofilm, but cannot penetrate the “slime”. NF-κ B is also responsible for the generation of amyloid-β (Aβ) which itself is anti-microbial. Aβ cannot penetrate the biofilm either, and its accumulation leads to destruction of the cerebral neurocircuitry. Treatment with penicillin (as in tertiary syphilis, the comparator to AD) is outlined; a biofilm dispersing agent may …need to be added to the protocol. Show more

Keywords: Amyloid-β, biofilm, innate immunity, spirochetes, treatment

DOI: 10.3233/JAD-160388

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1271-1276, 2016

Authors: Brønnick, Kolbørn | Breitve, Monica H. | Rongve, Arvid | Aarsland, Dag

Article Type: Research Article

Abstract: Background: The cognitive profile of mild dementia with Lewy bodies (DLB) versus mild Alzheimer’s disease (AD) has not been extensively studied, and the relation of cognitive deficits to the core diagnostic criteria for DLB (fluctuations, visual hallucinations, and parkinsonism) remains poorly understood. Objective: To compare the cognitive profile in patients with mild DLB to patients with mild AD and investigate the relation between cognitive deficits distinguishing DLB from AD and the core diagnostic features in DLB. Methods: Patients with mild dementia were recruited from the southwestern part of Norway and patients diagnosed with probable AD …(n  = 113) or probable DLB (n  = 77) were included. The DLB core diagnostic symptoms were assessed using standardized clinical measures, and standardized neurocognitive tests assessing attention, language, memory, and visuospatial functions were administered. Univariate and multivariate comparisons of cognitive tests were performed, and tests distinguishing between AD and DLB were subjected to correlational analyses with the core diagnostic symptoms. Results: DLB patients performed worse than AD patients on test of visuoconstruction, but not visual perception and on all tests involving attention and executive functions, except verbal fluency. The multivariate model distinguished between DLB and AD with a sensitivity of 74% and a specificity of 82%. Tests where DLB performed worse than AD were highly correlated with degree of parkinsonism, but not with cognitive fluctuations or visual hallucinations. Conclusions: The cognitive profile in mild DLB can be useful in distinguishing AD from DLB. The strong relation between relative deficits in DLB and parkinsonism warrants further studies. Show more

Keywords: Alzheimer’s disease, cognition, dementia, Lewy body dementia, parkinsonism

DOI: 10.3233/JAD-160294

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1277-1285, 2016

Authors: Vijverberg, Everard G.B. | Wattjes, Mike P. | Dols, Annemiek | Krudop, Welmoed A. | Möller, Christiane | Peters, Anne | Kerssens, Cora J. | Gossink, Flora | Prins, Niels D. | Stek, Max L. | Scheltens, Philip | van Berckel, Bart N.M. | Barkhof, Frederik | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: Background: Neuroimaging has a reasonable accuracy to differentiate behavioral variant frontotemporal dementia (bvFTD) from other neurodegenerative disorders, its value for the differentiation of bvFTD among subjects with acquired behavioral disturbances is unknown. Objective: To determine the diagnostic accuracy of MRI, additional [18 F]FDG-PET, and their combination for bvFTD among subjects with late onset behavioral changes. Methods: Patients with late onset behavioral changes referred to a memory clinic or psychiatric services were included. At baseline, 111 patients had a brain MRI scan and 74 patients received an additional [18 F]FDG-PET when the MRI was inconclusive. The …consensus diagnosis after two-year-follow-up was used as the gold standard to calculate sensitivity and specificity for baseline neuroimaging. Results: 27 patients had probable/definite bvFTD and 84 patients had a non-bvFTD diagnosis (primary psychiatric diagnosis or other neurological disorders). MRI had a sensitivity of 70% (95% CI 52–85%) with a specificity of 93% (95% CI 86–97%). Additional [18 F]FDG-PET had a sensitivity of 90% (95% CI 66–100%) with a specificity of 68% (95% CI 56–79%). The sensitivity of combined neuroimaging was 96% (95% CI 85–100%) with a specificity of 73% (95% CI 63–81%). In 66% of the genetic FTD cases, MRI lacked typical frontotemporal atrophy. 40% of cases with a false positive [18 F]FDG-PET scan had a primary psychiatric diagnosis. Conclusion: A good diagnostic accuracy was found for MRI and additional [18 F]FDG-PET for bvFTD in patients with late onset behavioral changes. Caution with the interpretation of neuroimaging results should especially be taken in cases with a genetic background and in cases with a primary psychiatric differential diagnosis where [18 F]FDG-PET is the only abnormal investigation. Show more

Keywords: Behavior, diagnostic accuracy, frontotemporal dementia, MRI, neuropsychology, psychiatric disorders

DOI: 10.3233/JAD-160285

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1287-1297, 2016

Authors: Ben-Sadoun, Grégory | Sacco, Guillaume | Manera, Valeria | Bourgeois, Jérémy | König, Alexandra | Foulon, Pierre | Fosty, Baptiste | Bremond, François | d’Arripe-Longueville, Fabienne | Robert, Philippe

Article Type: Research Article

Abstract: Background: The use of Serious exerGames (SeG) as enriched environments (EE), which promotes cognitive simulation with physical activity in a positive emotional context, has been proposed to represent a powerful method to slow down the decline due to neurodegenerative diseases (ND), such as Alzheimer’s disease (AD). However, so far, no SeG targeting EE has been tested in ND subjects. Objective: This study aimed at evaluating the usability and short-term training effects of X-Torp, an action SeG designed for elderly ND subjects with mild cognitive impairment (MCI) and AD. Methods: X-Torp is a SeG played using …the Microsoft® Kinect™. 10 ND subjects and 8 healthy elderly controls (HEC) were enrolled in a 1-month program with three training sessions per week. Usability was evaluated through game time, game performance, the aerobic intensity level reached, perceived emotions, and perceived usability. Results: All participants successfully completed the training program. ND subjects played less and had a lower game performance compared to HEC. During the sessions, ND subjects maintained a light intensity of aerobic activity, while HEC maintained a moderate intensity. Both groups experienced only positive emotions, and reported a ‘moderate’ to ‘high’ perceived competence, a ‘moderate’ game difficulty, and a ‘high’ interest in the game. Conclusion: Usability results suggest that X-Torp represents a usable EE for healthy subjects and persons with MCI and AD. However, in order to reach moderate or high intensity of aerobic activity, X-Torp control modes should be adapted to become more physically stimulating. Show more

Keywords: Aerobic activity, Alzheimer’s disease, cognition, enriched environment, mild cognitive impairment, sep serious game

DOI: 10.3233/JAD-160268

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1299-1314, 2016

Authors: Wilker, Elissa H. | Martinez-Ramirez, Sergi | Kloog, Itai | Schwartz, Joel | Mostofsky, Elizabeth | Koutrakis, Petros | Mittleman, Murray A. | Viswanathan, Anand

Article Type: Research Article

Abstract: Background: Long-term exposure to ambient air pollution has been associated with impaired cognitive function and vascular disease in older adults, but little is known about these associations among people with concerns about memory loss. Objective: To examine associations between exposures to fine particulate matter and residential proximity to major roads and markers of small vessel disease. Methods: From 2004–2010, 236 participants in the Massachusetts Alzheimer’s Disease Research Center Longitudinal Cohort participated in neuroimaging studies. Residential proximity to major roads and estimated 2003 residential annual average of fine particulate air pollution (PM2.5 ) were linked to …measures of brain parenchymal fraction (BPF), white matter hyperintensities (WMH), and cerebral microbleeds. Associations were modeled using linear and logistic regression and adjusted for clinical and lifestyle factors. Results: In this population (median age [interquartile range] = 74 [12 ], 57% female) living in a region with median 2003 PM2.5 annual average below the current Environmental Protection Agency (EPA) standard, there were no associations between living closer to a major roadway or for a 2μg/m3 increment in PM2.5 and smaller BPF, greater WMH volume, or a higher odds of microbleeds. However, a 2μg/m3 increment in PM2.5 was associated with –0.19 (95% Confidence Interval (CI): –0.37, –0.005) lower natural log-transformed WMH volume. Other associations had wide confidence intervals. Conclusions: In this population, where median 2003 estimated PM2.5 levels were below the current EPA standard, we observed no pattern of association between residential proximity to major roads or 2003 average PM2.5 and greater burden of small vessel disease or neurodegeneration. Show more

Keywords: Air pollution, microbleeds, small vessel disease, white matter hyperintensities

DOI: 10.3233/JAD-151143

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1315-1323, 2016

Authors: Pietto, Marcos | Parra, Mario A. | Trujillo, Natalia | Flores, Facundo | García, Adolfo M. | Bustin, Julian | Richly, Pablo | Manes, Facundo | Lopera, Francisco | Ibáñez, Agustín | Baez, Sandra

Article Type: Research Article

Abstract: Deficits in visual short-term memory (VSTM) binding have been proposed as an early and specific marker for Alzheimer’s disease (AD). However, no studies have explored the neural correlates of this domain in clinical categories involving prodromal stages with different risk levels of conversion to AD. We assessed underlying electrophysiological modulations in patients with mild cognitive impairment (MCI), patients in the MCI stages of familial AD carrying the mutation E280A of the presenilin-1 gene (MCI-FAD), and healthy controls. Moreover, we compared the behavioral performance and neural correlates of both patient groups. Participants completed a change-detection VSTM task assessing recognition of changes …between shapes or shape-color bindings, presented in two consecutive arrays (i.e., study and test) while event related potentials (ERPs) were recorded. Changes always occurred in the test array and consisted of new features replacing studied features (shape-only) or features swapping across items (shape-color binding). Both MCI and MCI-FAD patients performed worse than controls in the shape-color binding condition. Early electrophysiological activity (100–250 ms) was significantly reduced in both clinical groups, particularly over fronto-central and parieto-occipital regions. However, shape-color binding performance and their reduced neural correlates were similar between MCI and MCI-FAD. Our results support the validity of the VSTM binding test and their neural correlates in the early detection of AD and highlight the importance of studies comparing samples at different risk for AD conversion. The combined analysis of behavioral and ERP data gleaned with the VSTM binding task can offer a valuable memory biomarker for AD. Show more

Keywords: Electroencephalogram (EEG), event related potentials (ERPs), familial Alzheimer’s disease, memory binding, mild cognitive impairment, short-term memory

DOI: 10.3233/JAD-160056

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1325-1340, 2016

Authors: Garre-Olmo, Josep | Garcia-Ptacek, Sara | Calvó-Perxas, Laia | Turró-Garriga, Oriol | López-Pousa, Secundino | Eriksdotter, Maria

Article Type: Research Article

Abstract: The aim of this study was to compare the frequency of dementia diagnoses from two dementia registries in Europe. Patients registered between 2007 and 2013 in the Swedish Dementia Registry (SveDem; Sweden) and in the Registry of Dementias of Girona (ReDeGi; North-East of Spain) were selected. We compared sociodemographic data, Mini-Mental State Examination (MMSE) scores, dementia subtype, and medication consumption of 22,384 cases from SveDem and 5,032 cases from ReDeGi. The average age (78.1 years SveDem versus 79.7 years ReDeGi) and the gender (female 58.2% SveDem versus 61.5% ReDeGi) did not greatly differ. MMSE score at diagnosis was higher for …SveDem cases (22.1 versus 17.8). Alzheimer’s disease (AD) accounted for the main dementia subtype (36.6% SveDem versus 55.6% ReDeGi). The proportion of vascular dementia (VaD) and mixed dementia was higher in SveDem (18.8% versus 6.4% and 24.9 versus 13.4%), with an odds ratio (OR) and 95% confidence interval (CI) for SveDem relative to the ReDeGi of 3.41 (3.03–3.84) for VaD, and 2.15 (1.97–2.35) for mixed dementia. This was at the expense of a lower frequency of AD in SveDem (OR 0.41; 95% CI 0.39–0.44). Other dementia diagnoses such as frontotemporal dementia or dementia with Lewy bodies did not significantly differ between registries (2.3% versus 2.9%; 1.9 versus 3.1%). Large differences in medication consumption at the time of dementia diagnosis were detected (4.7 treatments SveDem versus 6.8 ReDeGi). Northern and southern European dementia cohorts differ in demographic characteristics, MMSE score at diagnosis, and drug treatment profile. Show more

Keywords: Alzheimer’s diseae, dementia, epidemiology, registries

DOI: 10.3233/JAD-160098

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1341-1351, 2016

Authors: Andersson, Carl-Henrik | Hansson, Oskar | Minthon, Lennart | Andreasen, Niels | Blennow, Kaj | Zetterberg, Henrik | Skoog, Ingmar | Wallin, Anders | Nilsson, Staffan | Kettunen, Petronella

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder represented by the accumulation of intracellular tau protein and extracellular deposits of amyloid-β (Aβ) in the brain. The gene sortilin 1 (SORT1 ) has previously been associated with cardiovascular disease in gene association studies. It has also been proposed to be involved in AD pathogenesis through facilitating Aβ clearance by binding apoE/Aβ complexes prior to cellular uptake. However, the neuropathological role of SORT1 in AD is not fully understood. To evaluate the associations between gene variants of SORT1 and risk of AD, we performed genetic analyses in a Swedish case-control cohort. …Ten single nucleotide polymorphisms (SNPs), covering the whole SORT1 gene, were selected and genotyped in 620 AD patients and 1107 controls. The SNP rs17646665, located in a non-coding region of the SORT1 gene, remained significantly associated with decreased risk of AD after multiple testing (pc  = 0.0061). In addition, other SNPs were found to be nominally associated with risk of AD, as well as altered cognitive function and the CSF biomarker Aβ42 , but these associations did not survive correction for multiple testing. The fact that SORT1 has been strongly associated with risk of cardiovascular disease is intriguing as cardiovascular disease is also regarded as a risk factor for AD. Finally, increased knowledge about SORT1 function has a potential to increase our understanding of APOE , the strongest risk factor for AD. Show more

Keywords: Amyloid beta-peptides, apolipoprotein E, biomarkers, genetic association studies, genotype, neuropsychological tests, risk factors, single nucleotide polymorphism, tau proteins, vesicular transport adaptor proteins

DOI: 10.3233/JAD-160319

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1353-1363, 2016