Journal of Alzheimer's Disease - Volume 64, issue 2

Authors: Posporelis, Sotirios | David, Anthony S. | Ashkan, Keyoumars | Shotbolt, Paul

Article Type: Review Article

Abstract: Deep brain stimulation (DBS) is an effective invasive treatment for a wide range of neurological and psychiatric disorders. Neurosurgically implanted electrodes deliver stimulation of pre-programmed amplitude, frequency, and pulse width within deep brain structures; those settings can be adjusted at a later stage according to individual needs for optimal response. This results in variable effects dependent on the targeted region. An established treatment for movement disorders, the effectiveness of DBS in dementia remains under investigation. Translational studies have uncovered a pro-cognitive effect mediated by changes on cellular as well as network level. Several groups have attempted to examine the benefits …of DBS in Alzheimer’s disease; differences in inclusion criteria and methodology make generalization of results difficult. This review aims to summarize all completed and ongoing human studies of DBS in Alzheimer’s disease. The results are classified by targeted anatomical structure. Future directions, as well as economical and ethical arguments, are explored in the final section. Show more

Keywords: Alzheimer’s disease, deep brain stimulation, dementia, memory, neuromodulation, neuropsychiatry

DOI: 10.3233/JAD-180212

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 337-347, 2018

Authors: Bussè, Cinzia | Caffarra, Paolo | Rossi, Alice | Zorzi, Giovanni | Fragiacomo, Federica | Camporese, Giulia | Pompanin, Sara | Di Bernardo, Gian Antonio | Cagnin, Annachiara

Article Type: Short Communication

Abstract: The Free and Cued Selective Reminding test (FCSRT) was used to assess memory in 19 patients with prodromal dementia with Lewy bodies (DLB) and 25 Alzheimer’s disease (AD) patients. DLB scored better than AD in selective measures of the FCSRT: immediate total recall (p = 0.01) and index of sensitivity of cueing (p = 0.001), while free delayed and total memory scores were similarly impaired. The index of sensitivity of cueing held a sensitivity of 76% and specificity of 79% in distinguishing DLB. FCSRT could help in disentangling hippocampal memory deficits from memory impairment due to ineffective recall …strategies. Show more

Keywords: Alzheimer’s disease, dementia with Lewy bodies, hippocampus, memory

DOI: 10.3233/JAD-180166

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 349-353, 2018

Authors: Brookes, Keeley J. | McConnell, George | Williams, Kirsty | Chaudhury, Sultan | Madhan, Gaganjit | Patel, Tulsi | Turley, Christopher | Guetta-Baranes, Tamar | Bras, Jose | Guerreiro, Rita | Hardy, John | Francis, Paul T. | Morgan, Kevin

Article Type: Short Communication

Abstract: The Brains for Dementia Research project is a recently established longitudinal cohort which aims to provide brain tissue for research purposes from neuropathologically defined samples. Here we present the findings from our analysis on the 19 established GWAS index SNPs for Alzheimer’s disease, in order to demonstrate if the BDR sample also displays association to these variants. A highly significant association of the APOE ɛ 4 allele was identified (p = 3.99×10–12 ). Association tests for the 19 GWAS SNPs found that although no SNPs survive multiple testing, nominal significant findings were detected and concordance with the Lambert …et al. GWAS meta-analysis was observed. Show more

Keywords: Alzheimer’s disease, association, Brains for Dementia Research, genome-wide association study, single nucleotide polymorphisms

DOI: 10.3233/JAD-180191

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 355-362, 2018

Authors: Itzhaki, Ruth F. | Lathe, Richard

Article Type: Article Commentary

Abstract: Three articles have very recently appeared that are of especial relevance to the causes of dementia and its potential treatment. The first two (Tsai et al., published in PLoS One in November 2017; Chen et al., published in the January/February 2018 issue of Journal of Clinical Psychiatry ) demonstrate an increased risk of subsequent senile dementia (SD) development in patients with acute varicella zoster (herpes zoster) infection. These articles present data highly relevant to the third, and most important, paper—by Tzeng et al., published online in the journal Neurotherapeutics at the end of February 2018. These authors report …that infection with a different herpes virus, herpes simplex virus type 1 (HSV1), leads to a similarly increased risk of later developing SD. Further, when the authors looked at patients treated aggressively with antiherpetic medications at the time, the relative risk of SD was reduced by a factor of 10. It should be stressed that no investigations were made on subjects already suffering from SD, and that those treated were the few rare cases severely affected by HSV. Nonetheless, antiherpetic medication prevented later SD development in 90% of their study group. These articles provide the first population evidence for a causal link between herpes virus infection and senile dementia. Show more

Keywords: Alzheimer’s disease, antiherpetic medication, causal link, herpes simplex virus, population epidemiology, varicella zoster virus

DOI: 10.3233/JAD-180266

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 363-366, 2018

Authors: Nolan, John M. | Mulcahy, Riona | Power, Rebecca | Moran, Rachel | Howard, Alan N.

Article Type: Research Article

Abstract: Background: A growing body of scientific evidence suggests that enrichment of certain nutritional compounds in the brain may reduce the risk of Alzheimer’s disease (AD). Objective: To investigate the impact of supplemental xanthophyll carotenoids plus omega-3 fatty acids on disease progression in patients with AD. Methods: Three trial experiments were performed. In Trials 1 and 2 (performed on patients with AD over an 18-month period), 12 patients (AD status at baseline: 4 mild and 8 moderate) were supplemented with a xanthophyll carotenoid only formulation (Formulation 1; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day) and 13 patients (AD status at baseline: 2 …mild, 10 moderate, and 1 severe) were supplemented with a xanthophyll carotenoid and fish oil combination (Formulation 2; lutein:meso-zeaxanthin:zeaxanthin 10:10:2 mg/day plus 1 g/day of fish oil containing 430 mg docohexaenoic acid [DHA] and 90 mg eicopentaenoic acid [EPA]), respectively. In Trial 3, 15 subjects free of AD (the control group) were supplemented for 6 months with Formulation 1. Blood xanthophyll carotenoid response was measured in all trials by HPLC. Omega-3 fatty acids were profiled by direct infusion mass spectrometry. Results: Xanthophyll carotenoid concentration increases were significantly greater for Formulation 2 compared to Formulation 1 (p  < 0.05), and progression of AD was less for this group (p  = 0.003), with carers reporting functional benefits in memory, sight, and mood. Conclusion: This preliminary report suggests positive outcomes for patients with AD who consumed a combination of xanthophyll carotenoids plus fish oil, but further study is required to confirm this important observation. Show more

Keywords: Alzheimer’s disease, dementia, DHA, fatty acids, lutein, meso-zeaxanthin, nutrition, omega-3, prevention, xanthophyll carotenoids

DOI: 10.3233/JAD-180160

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 367-378, 2018

Authors: Schmöle, Anne-Caroline | Lundt, Ramona | Toporowski, Gregor | Hansen, Jan N. | Beins, Eva | Halle, Annett | Zimmer, Andreas

Article Type: Research Article

Abstract: It is widely accepted that the endocannabinoid system (ECS) is a modulator of neuroinflammation associated with neurodegenerative disorders, including Alzheimer’s disease (AD). Thus, expression of the cannabinoid receptor 2 (CB2) is induced in plaque-associated microglia and astrocytes in brain tissues from AD patients and in genetic mouse models expressing pathogenic variants of the amyloid precursor protein (APP). However, the exact mechanism of CB2 signaling in this mouse model remains elusive, because the genetic deletion of CB2 and the pharmacological activation of CB2 both reduced neuroinflammation. Here, we demonstrate that CB2 deletion also improved cognitive and learning deficits in APP/PS1*CB2–/– …mice. This was accompanied by reduced neuronal loss and decreased plaque levels and coincided with increased expression of Aβ degrading enzymes. Interestingly, plaque-associated microglia in APP/PS1*CB2–/– mice showed a less activated morphology, while plaques were smaller and more condensed than in APP/PS1 mice. Taken together, these results indicate a beneficial effect of CB2-deficiency in APP transgenic mice. CB2 appears to be part of a protective system that may be detrimental when engaged continuously. Show more

Keywords: Alzheimer’s disease, CB2, endocannabinoid system, microglia, neuroinflammation

DOI: 10.3233/JAD-180230

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 379-392, 2018

Authors: Tiepolt, Solveig | Schäfer, Andreas | Rullmann, Michael | Roggenhofer, Elisabeth | Netherlands Brain Bank | Gertz, Hermann-Josef | Schroeter, Matthias L. | Patt, Marianne | Bazin, Pierre-Louis | Jochimsen, Thies H. | Turner, Robert | Sabri, Osama | Barthel, Henryk

Article Type: Research Article

Abstract: Background: PET imaging is an established technique to detect cerebral amyloid-β (Aβ) plaques in vivo . Some preclinical and postmortem data report an accumulation of redox-active iron near Aβ plaques. Quantitative susceptibility mapping (QSM) at high-field MRI enables iron deposits to be depicted with high spatial resolution. Objective: Aim of this study was to examine whether iron and Aβ plaque accumulation is related and thus, whether 7T MRI might be an additive diagnostic tool to Aβ PET imaging. Methods: Postmortem human Alzheimer’s disease (AD) and healthy control (HC) frontal gray matter (GM) was imaged with 7T …MRI which resulted in T1 maps and QSM. Aβ plaque load was determined by histopathology. In vivo , 10 Aβ PET-positive AD patients (74.1±6.0a) and 10 Aβ PET-negative HCs (67.1±4.4a) underwent 7T MR examination and QSM maps were analyzed. Severity of cognitive deficits was determined by MMSE. Results: Postmortem, the susceptibility of Aβ plaque-containing GM were higher than those of Aβ plaque-free GM (0.011±0.002 versus – 0.008±0.003 ppm, p  < 0.001). In vivo , only the bilateral globus pallidus showed significantly higher susceptibility in AD patients compared to HCs (right: 0.277±0.018 versus – 0.009±0.009 ppm; left: 0.293±0.014 versus – 0.007±0.012 ppm, p  < 0.0001). The pallidal QSM values were negatively correlated with those of the MMSE (r  = – 0.69, p  = 0.001). Conclusion: The postmortem study revealed significant susceptibility differences between the Aβ plaque-containing and Aβ plaque-free GM, whereas in vivo only the QSM values of the globus pallidus differed significantly between AD and HC group. The pallidal QSM values correlated with the severity of cognitive deficits. These findings encourage efforts to optimize the 7T-QSM methodology. Show more

Keywords: Alzheimer’s disease, amyloid, iron accumulation, quantitative susceptibility mapping, 7T MRI

DOI: 10.3233/JAD-180118

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 393-404, 2018

Authors: Scherr, Martin | Pasquini, Lorenzo | Benson, Gloria | Nuttall, Rachel | Gruber, Martin | Neitzel, Julia | Brandl, Felix | Sorg, Christian | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Both ongoing local metabolic activity (LMA) and corresponding functional connectivity (FC) with remote brain regions are progressively impaired in Alzheimer’s disease (AD), particularly in the posterior default mode network (pDMN); however, it is unknown how these impairments interact. It is well known that decreasing mean synaptic activity of a region, i.e., decreasing LMA, reduces the region’s sensitivity to afferent input from other regions, i.e., FC. Objective: We hypothesized progressive decoupling between LMA and FC in AD, which is linked to amyloid-β pathology (Aβ). Methods: Healthy adults (n =20) and Aβ+patients without memory impairment (n =9), …early MCI (n =21), late MCI (n =18) and AD (n =22) were assessed by resting-state fMRI, FDG-PET, and AV-45-PET to measure FC, LMA, and Aβ of the pDMN. Coupling between LMA and FC (rLA/FC ) was estimated by voxelwise correlation. Results: RLMA/FC decreased with disease severity (F =20.09, p <0.001). This decrease was specifically associated with pDMN Aβ (r =−0.273, p =0.029) but not global Aβ (r =−0.112, p =0.378) and with the impact of Aβ on FC (i.e., rAβ/FC, r =−0.339; p =0.006). In multiple regression models rLMA/FC was also associated with memory impairment, reduced cognitive speed and flexibility, outperforming global Aβ, pDMN Aβ, pDMN LMA, and pDMN FC, respectively. Conclusion: Results demonstrate increasing decoupling of LMA from its FC in AD. Data suggest that decoupling is driven by local Aβ and contributes to memory decline. Show more

Keywords: Alzheimer’s disease, amyloid-β, default mode network, functional connectivity, local metabolic activity

DOI: 10.3233/JAD-180022

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 405-415, 2018

Authors: Furcila, Diana | DeFelipe, Javier | Alonso-Nanclares, Lidia

Article Type: Research Article

Abstract: The main pathological hallmarks in Alzheimer’s disease (AD) are the presence of extracellular amyloid plaques, primarily consisting of amyloid-β (Aβ) peptide, and the accumulation of paired helical filaments of hyperphosphorylated tau protein (PHF-Tau ) within neurons. Since CA1 is one of the most affected regions in AD, mainly at early stages, we have performed a detailed analysis of the CA1 region from 11 AD patients (demented and clinically similar; Braak stages IV-VI) to better understand the possible relationship between the presence and distribution of different neurochemical types of Aβ plaques and PHF-Tau immunoreactive  (- ir)  neurons. Hence, we have …examined hippocampal sections in confocal microscopy images from double and triple-immunostained sections, to study labeled plaques and PHF-Tau-ir neurons using specific software tools. There are four main findings in the present study. First, the pyramidal layer of proximal CA1 (close to CA2) contains the smallest number of both plaques and PHF-Tau-ir neurons. Second, a large proportion of Aβ-ir plaques were also characterized by the presence of PHF-Tau-ir . Third, all plaques containing one of the two PHF-Tau isoforms also express the other isoform, that is, if a plaque contains PHFpS396 , it also contains PHFAT8 , and vice versa. Fourth, the coexpression study of both PHF-Tau isoforms in CA1 neurons revealed that most of the labeled neurons express only PHFpS396 . Our findings further support the idea that AD is not a unique entity even within the same neuropathological stage, since the microanatomical/neurochemical changes that occur in the hippocampus greatly vary from one patient to another. Show more

Keywords: Confocal microscopy, hippocampal CA1 field, immunofluorescence, methoxy-X04, neurofibrillary tangles, senile plaques, tau protein

DOI: 10.3233/JAD-180173

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 417-435, 2018

Authors: Järvinen, Heli | Taipale, Heidi | Koponen, Marjaana | Tanskanen, Antti | Tiihonen, Jari | Tolppanen, Anna-Maija | Hartikainen, Sirpa

Article Type: Research Article

Abstract: Background: Persons with Alzheimer’s disease (AD) are frequently hospitalized from infection-related causes. There are no previous studies investigating hospitalization associated with antibiotic initiation in persons with AD. Objective: To investigate the frequency and risk of hospitalization associated with oral antibiotic initiation among community dwellers with and without AD. Methods: We performed a retrospective register-based study utilizing register-based Medication Use and Alzheimer’s disease (MEDALZ) cohort. It includes all community dwellers diagnosed with AD during 2005–2011 in Finland and their matched comparison persons without AD. Antibiotic use was initiated by 34,785 persons …with and 36,428 without AD. Drug use data were collected from Prescription Register and comorbidities from Special Reimbursement and Hospital Care Registers. Infection diagnoses were collected from the Hospital Care Register. Factors associated with hospitalization were estimated utilizing logistic regression models. Results: Risk of hospitalization following antibiotic initiation was higher among antibiotic initiators with AD than without AD (adjusted odds ratio, aOR, 1.37, 95% Cl 1.28–1.46). Strongest association with hospitalization was found for oral glucocorticoid use, aOR 1.41 (1.25–1.59); epilepsy, aOR 1.33 (1.10–1.63); and active cancer, aOR 1.30 (1.14–1.49). Among initiators of cephalexin, pivmecillinam, amoxicillin/amoxicillin, and enzyme inhibitor and doxycycline, persons with AD were more frequently hospitalized than persons without AD. A quarter of hospitalized antibiotic initiators had infection diagnosis in their hospital care records. Conclusions: Persons with AD initiating an antibiotic had a higher risk for hospitalization than antibiotic initiators without AD. Further research is needed to determine whether infection-related hospitalization could be reduced. Show more

Keywords: Alzheimer’s disease, antibiotic, dementia, hospitalization, infection, pharmacoepidemiology

DOI: 10.3233/JAD-180125

Citation: Journal of Alzheimer's Disease, vol. 64, no. 2, pp. 437-445, 2018