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

Authors: David, Renaud | Manera, Valeria | Fabre, Roxane | Pradier, Christian | Robert, Philippe | Tifratene, Karim

Article Type: Research Article

Abstract: Background: Safety warnings from health authorities are currently intended to limit the use of psychotropic agents in dementia-related conditions. Evidence concerning the use of antidepressants in dementia is, however, scarce and contradictory. Objective: To evaluate antidepressant use among individuals with Alzheimer’s disease (AD) and related disorders in the French population between 2010 and 2014. Method: Antidepressant prescriptions in individuals with AD, mixed dementia (MD), and vascular dementia (VaD) in the French National Alzheimer Database between 2010 and 2014 were analyzed (N  = 199,544). Results: Multivariate analysis showed an annual significant increase (p  < 0.001) in …the prescription rate of antidepressants from 26% (2010) to 31% (2014), and identified female gender, younger age, higher education, living in long-term facilities, more severe cognitive decline, and presence of vascular signs (VaD and MD) as associated factors for antidepressant prescribing. Conclusion: The annual increase of antidepressant prescribing among individuals with AD, MD, and VaD in French specialized settings may be partially related to the lack of current valuable medications for dementia-related behavioral symptoms. Show more

Keywords: Alzheimer’s disease, antidepressant, dementia, psychotropic medication

DOI: 10.3233/JAD-160238

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1365-1373, 2016

Authors: Naro, Antonino | Corallo, Francesco | De Salvo, Simona | Marra, Angela | Di Lorenzo, Giuseppe | Muscarà, Nunzio | Russo, Margherita | Marino, Silvia | De Luca, Rosaria | Bramanti, Placido | Calabrò, Rocco Salvatore

Article Type: Research Article

Abstract: The differential diagnosis of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) is not always straightforward, and the rate of progression of MCI to dementia is not negligible. Thus, there is a need for para-clinical approaches that can improve the differential diagnosis and identify patients that are at risk of progression. There is a growing interest, at present, in the role of the deterioration of brain oscillations as a predictor of MCI-to-AD conversion. For this reason, we experimentally modulated γ -band oscillations (GBO) in a sample of MCI and AD patients and an age-matched healthy elderly group, using a transcranial …alternating current stimulation (tACS) protocol that was applied to different cortical sites. We correlated the after-effects of tACS on the GBO and the neuropsychological data, in an attempt to differentiate MCI from AD patients and identify, among the MCI patients, those that could be at potential risk of MCI-to-dementia conversion. MCI patients showed a partial GBO increase and improvement in some neuropsychological tests whereas AD individuals did not show significant tACS after-effects. Notably, some MCI subjects lacked significant neuropsychological and electrophysiological after-effects, similar to AD individuals. In a two-year follow-up, such MCI individuals had converted into AD. Therefore, our data suggest that tACS may support the clinical differential diagnosis of MCI and AD and identify MCI patients who could be at risk of developing dementia. This prediction index may help the clinician to adopt a better prevention/follow-up strategy in such a disabling neurodegenerative disease. Show more

Keywords: Alzheimer’s disease, gamma-band oscillations, mild cognitive impairment, transcranial alternating current stimulation

DOI: 10.3233/JAD-160305

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1375-1388, 2016

Authors: Rossini, Paolo Maria | Di Iorio, Riccardo | Granata, Giuseppe | Miraglia, Francesca | Vecchio, Fabrizio

Article Type: Article Commentary

Abstract: In a recent study, analyzing the modulation of γ-band oscillations, Naro and colleagues demonstrated that transcranial alternating current stimulation could drive the gamma rhythms in the human EEG in cognitive healthy elderly subjects but not in mild cognitive impairment (MCI) prodromal to Alzheimer’s disease (AD) and in early AD patients. Therefore, this method is proposed to intercept early in the disease course those MCI subjects who are in a pre-symptomatic stage of an already established AD. This prediction index may help the clinician to adopt a better prevention/follow-up strategy. In this direction, the novel advances in EEG analysis for the …evaluation of brain reactivity and connectivity-namely via innovative mathematical approach, i.e., graph theory-represent a promising tool for a non-invasive and easy-to-perform neurophysiological marker that could be used for the pre-symptomatic diagnosis of AD and to predict MCI progression to dementia. Show more

Keywords: Alzheimer’s disease, effective connectivity, electroencephalography, functional connectivity, graph theory, mild cognitive impairment, non-invasive brain stimulation

DOI: 10.3233/JAD-160482

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1389-1393, 2016

Authors: Penninkilampi, Ross | Brothers, Holly M. | Eslick, Guy D.

Article Type: Research Article

Abstract: Background: Drugs targeting γ-secretase in Alzheimer’s disease (AD) have failed to demonstrate efficacy in clinical trials. Objective: To perform a meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of drugs targeting γ-secretase in AD. Methods: Ten trials were identified involving 5,227 patients using electronic databases and manual review of reference lists. RCTs of at least two weeks duration involving a drug targeting γ-secretase were eligible. The main outcomes examined were adverse events and cognitive measures (ADAS-cog, MMSE, ADCS-ADL, and CDR-sb). A sub-group analysis was performed, excluding the γ-secretase modulator tarenflurbil, to …evaluate the safety and efficacy of γ-secretase inhibitors only. Results: There was an increased risk of adverse events (Odds Ratio (OR) 1.38, 95% CI 1.09–1.73; p  = 0.01), serious adverse events (OR 1.50, 95% CI 1.22–1.84; p  < 0.001), and skin cancers (OR 4.77, 95% CI 2.83–8.06; p  < 0.001). There was significantly increased risk of infections (OR 1.36, 95% CI 1.13–1.63; p  < 0.001) in the subgroup analysis excluding tarenflurbil. Pooled results also revealed a worsening in ADAS-cog (difference in means 1.33, 95% CI 0.58–2.08; p  < 0.001) and MMSE (difference in means –0.66, 95% CI –0.96 to 0.35; p  < 0.001), but not ADCS-ADL or CDR-sb. Conclusion: The use of γ-secretase inhibitors is associated with significantly increased risk of serious adverse events including skin cancers, and worsening in cognitive indicators. This evidence indicates that γ-secretase may not be an appropriate target for clinical treatment of AD. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, avagacestat, gamma-secretase, meta-analysis, semagacestat, tarenflurbil

DOI: 10.3233/JAD-160275

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1395-1404, 2016

Authors: Idrizbegovic, Esma | Hederstierna, Christina | Rosenhall, Ulf

Article Type: Research Article

Abstract: Background: Cortical auditory event-related potentials (ERPs) were studied in order to measure mismatch negativity (MMN). Three groups of subjects were studied: patients with Alzheimer’s disease (AD, n  = 32), mild cognitive impairment (MCI, n  = 44), and subjective memory complaints without cognitive decline (SMC, n  = 27). A bottom up strategy was applied, and the right and left ears were stimulated monaurally. Objective: To investigate MMN in AD and MCI, and in a clinical reference group. Methods: ERPs were carried out with 500 tone pulses at 80 dBnHL. Each sequence included 80% standard tones (500 Hz) (f), and 20% …deviant tones (1000 Hz) (r). MMN measurements were carried out by comparing the amplitudes of (f) and (r) recordings and to calculate the amplitude difference in μ V for each group. The right and the left ears were analyzed separately. Results: A left ear advantage (LEA) of MMN amplitude was demonstrated in the two groups with better cognition (the MCI and the SMC groups), but not in the AD group. Discussion: The absence of MMN asymmetry in the AD group is possibly caused by a dysfunction to apprehend changes of tonal stimuli. Show more

Keywords: Central auditory processing disorders, cortical auditory event-related potentials, left ear advantage, right ear advantage, subjective memory complaints

DOI: 10.3233/JAD-160323

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1405-1410, 2016

Authors: Dumurgier, Julien | Dartigues, Jean-François | Gabelle, Audrey | Paquet, Claire | Prevot, Magali | Hugon, Jacques | Tzourio, Christophe

Article Type: Research Article

Abstract: Time disorientation is commonly observed in dementia, however very little is known about the pathological significance of minor time errors in community-dwelling population. Our objective was to investigate the relationship between time orientation and risk of dementia in a population of older adults. Analyses relies on 8611 dementia-free subjects from the Three-City Study, France. Participants were followed up for 10 years for incident dementia. Time orientation was assessed by asking for the date, the day of the week, the month, the season and the year. At baseline, 905 subjects made at least one error in time orientation. During 57,073 person-years …of follow-up, 827 participants developed dementia. After controlling for age, gender and education level, subjects with one error in time had a greater risk of dementia (hazard ratio [HR] 1.44 [1.18–1.77]), while those with at least 2 errors had a more than three-fold increased risk (HR 3.10 [1.98–4.83]). This association was particularly marked for the diagnosis of probable Alzheimer’s disease. Time disorientation was associated with an increased risk of dementia in a large population of cognitively normal older people followed during up to 10 years and should not be underestimated in clinical setting. Show more

Keywords: Epidemiology, dementia, time orientation, neuropsychology, aging

DOI: 10.3233/JAD-160295

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1411-1418, 2016

Authors: Deng, Yulei | Wei, Jing | Cheng, Jia | Zhong, Ping | Xiong, Zhe | Liu, Aiyi | Lin, Lin | Chen, Shengdi | Yan, Zhen

Article Type: Research Article

Abstract: The loss of synaptic structure and function has been linked to the cognitive impairment of Alzheimer’s disease (AD). Dysregulation of the actin cytoskeleton, which plays a key role in regulating the integrity of synapses and the transport of synaptic proteins, has been suggested to contribute to the pathology of AD. In this study, we found that glutamate receptor surface expression and synaptic function in frontal cortical neurons were significant diminished in a familial AD (FAD) model, which was correlated with the reduction of phosphorylated cofilin, a key protein regulating the dynamics of actin filaments. Injecting a cofilin dephosphorylation inhibitory peptide …to FAD mice led to the partial rescue of the surface expression of AMPA and NMDA receptor subunits, as well as the partial restoration of AMPAR- and NMDAR-mediated synaptic currents. Moreover, the impaired working memory and novel object recognition memory in FAD mice were partially ameliorated by injections of the cofilin dephosphorylation inhibitory peptide. These results suggest that targeting the cofilin-actin signaling holds promise to mitigate the physiological and behavioral abnormality in AD. Show more

Keywords: Actin, Alzheimer’s disease, cofilin, glutamate receptors, novel object recognition memory, prefrontal cortex, working memory

DOI: 10.3233/JAD-160167

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1419-1432, 2016

Authors: Abdullah, Mohammad | Takase, Hiroshi | Nunome, Mari | Enomoto, Hiroyuki | Ito, Jin-ichi | Gong, Jian-Sheng | Michikawa, Makoto

Article Type: Research Article

Abstract: Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-β (Aβ) from the brain. Aβ is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of Aβ on release of exosomes from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear Aβ from the brain, in the culture medium …of astrocytes. We found that exosome and apoE-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by Aβ1–42 treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apoE-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by Aβ treatment to levels similar to those of control, suggesting that Aβ1–42 inhibits exosome release via stimulation of JNK signal pathway. Because exosomes are shown to remove Aβ in the brain, our findings suggest that increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway. Show more

Keywords: Amyloid-β, astrocyte, exosome, flotillin, JNK

DOI: 10.3233/JAD-160292

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1433-1441, 2016

Authors: Salomon-Zimri, Shiran | Glat, Micaela Johanna | Barhum, Yael | Luz, Ishai | Boehm-Cagan, Anat | Liraz, Ori | Ben-Zur, Tali | Offen, Daniel | Michaelson, Daniel M.

Article Type: Research Article

Abstract: Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer’s disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α . We next set …to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42 , and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, behavior, hippocampus, lentivirus, Morris water maze, object recognition, targeted replacement mice, vascular endothelial growth factor

DOI: 10.3233/JAD-160182

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1443-1458, 2016

Authors: Miklossy, Judith

Article Type: Research Article

Abstract: It has long been known that spirochetes form clumps or micro colonies in vitro and in vivo. Cortical spirochetal colonies in syphilitic dementia were considered as reproductive centers for spirochetes. Historic and recent data demonstrate that senile plaques in Alzheimer’s disease (AD) are made up by spirochetes. Spirochetes, are able to form biofilm in vitro . Senile plaques are also reported to contain elements of biofilm constituents. We expected that AβPP and Aβ (the main components of senile plaques) also occur in pure spirochetal biofilms, and bacterial DNA (an important component of biofilm) is also present in senile …plaques. Histochemical, immunohistochemical, and in situ hybridization techniques and the TUNEL assay were used to answer these questions. The results obtained demonstrate that Aβ and DNA, including spirochete-specific DNA, are key components of both pure spirochetal biofilms and senile plaques in AD and confirm the biofilm nature of senile plaques. These results validate validate previous observations that AβPP and/or an AβPP-like amyloidogenic protein are an integral part of spirochetes, and indicate that bacterial and host derived Aβ are both constituents of senile plaques. DNA fragmentation in senile plaques further confirms their bacterial nature and provides biochemical evidence for spirochetal cell death. Spirochetes evade host defenses, locate intracellularly, form more resistant atypical forms and notably biofilms, which contribute to sustain chronic infection and inflammation and explain the slowly progressive course of dementia in AD. To consider co-infecting microorganisms is equally important, as multi-species biofilms result in a higher resistance to treatments and a more severe dementia. Show more

Keywords: Alzheimer’s disease, amyloid, AβPP, amyloid beta, bacteria, biofilm, Borrelia burgdorferi, colonies, chronic infection, spirochetes, thioflavin S, Treponema spirochetes

DOI: 10.3233/JAD-160451

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1459-1473, 2016