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

Authors: Glonnegger, Hannah | Beyle, Aline | Cerff, Bernhard | Gräber, Susanne | Csoti, Ilona | Berg, Daniela | Liepelt-Scarfone, Inga

Article Type: Research Article

Abstract: Background: There is need for multidimensional quantitative assessment of cognitive driven activities of daily living (ADL) functions in Parkinson’s disease (PD). Objective: To determine whether there is an ADL profile related to cognitive impairment in PD assessed by the Multiple Object Test (MOT). We assumed MOT performance to be lower in PD patients versus controls and in PD patients with more severe cognitive impairment. Methods: 50 PD patients with no cognitive impairment (PD-NC), 54 patients with PD-mild cognitive impairment (PD-MCI), 29 with Parkinson’s disease dementia (PDD), and 40 healthy controls (HC) were investigated. Besides comprehensive …cognitive testing, the MOT, a performance based test consisting of five routine tasks (e.g., preparing a cup of coffee), was applied. Quantitative (total errors and time) and qualitative (error type) MOT parameters were analyzed. Results: Total time and number of MOT errors was increased in PD patients compared to controls (p  < 0.001). These parameters also differentiated PDD patients from other cognitive groups (p  < 0.05). No control subject had ≥ 4 errors in the MOT, but 30% of PD patients, especially PDD, scored above this cut-off. Omission (p  < 0.001) and mislocation (p  < 0.03) errors were more prominent in PDD than other cognitive groups. Perplexity errors did not differ between PD-MCI and PDD but between PD-NC and PDD (p  = 0.01). MOT parameters discriminating between cognitive groups correlated mainly with lower test performance in psychomotor speed and executive function. Conclusion: Performance based testing is promising to identify quantitative and qualitative ADL aspects differentiating between different cognitive groups which might be helpful for an early detection of PDD. Show more

Keywords: Activities of daily living, cognition, dementia, Parkinson’s disease, performance-based assessment

DOI: 10.3233/JAD-160173

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1475-1484, 2016

Authors: Stravalaci, Matteo | Tapella, Laura | Beeg, Marten | Rossi, Alessandro | Joshi, Pooja | Pizzi, Erika | Mazzanti, Michele | Balducci, Claudia | Forloni, Gianluigi | Biasini, Emiliano | Salmona, Mario | Diomede, Luisa | Chiesa, Roberto | Gobbi, Marco

Article Type: Research Article

Abstract: 15B3 is a monoclonal IgM antibody that selectively detects pathological aggregates of the prion protein (PrP). We report the unexpected finding that 15B3 also recognizes oligomeric but not monomeric forms of amyloid-β (Aβ)42 , an aggregating peptide implicated in the pathogenesis of Alzheimer’s disease (AD). The 15B3 antibody: i) inhibits the binding of synthetic Aβ42 oligomers to recombinant PrP and neuronal membranes; ii) prevents oligomer-induced membrane depolarization; iii) antagonizes the inhibitory effects of oligomers on the physiological pharyngeal contractions of the nematode Caenorhabditis elegans ; and iv) counteracts the memory deficits induced by intracerebroventricular injection of Aβ42 oligomers …in mice. Thus this antibody binds to pathologically relevant forms of Aβ, and offers a potential research, diagnostic, and therapeutic tool for AD. Show more

Keywords: 15B3 antibody, Alzheimer’s disease, amyloid beta-protein (1– 42), oligomers, prion protein, prions, oligomers

DOI: 10.3233/JAD-150882

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1485-1497, 2016

Authors: Qosa, Hisham | Mohamed, Loqman A. | Al Rihani, Sweilem B. | Batarseh, Yazan S. | Duong, Quoc-Viet | Keller, Jeffrey N. | Kaddoumi, Amal

Article Type: Research Article

Abstract: The blood-brain barrier (BBB) is a dynamic interface that maintains brain homeostasis and protects it from free entry of chemicals, toxins, and drugs. The barrier function of the BBB is maintained mainly by capillary endothelial cells that physically separate brain from blood. Several neurological diseases, such as Alzheimer’s disease (AD), are known to disrupt BBB integrity. In this study, a high-throughput screening (HTS) was developed to identify drugs that rectify/protect BBB integrity from vascular amyloid toxicity associated with AD progression. Assessing Lucifer Yellow permeation across in-vitro BBB model composed from mouse brain endothelial cells (bEnd3) grown on 96-well plate …inserts was used to screen 1280 compounds of Sigma LOPAC®1280 library for modulators of bEnd3 monolayer integrity. HTS identified 62 compounds as disruptors, and 50 compounds as enhancers of the endothelial barrier integrity. From these 50 enhancers, 7 FDA approved drugs were identified with EC50 values ranging from 0.76–4.56 μM. Of these 7 drugs, 5 were able to protect bEnd3-based BBB model integrity against amyloid toxicity. Furthermore, to test the translational potential to humans, the 7 drugs were tested for their ability to rectify the disruptive effect of Aβ in the human endothelial cell line hCMEC/D3. Only 3 (etodolac, granisetron, and beclomethasone) out of the 5 effective drugs in the bEnd3-based BBB model demonstrated a promising effect to protect the hCMEC/D3-based BBB model integrity. These drugs are compelling candidates for repurposing as therapeutic agents that could rectify dysfunctional BBB associated with AD. Show more

Keywords: Amyloid-β , blood-brain barrier, high-throughput screening, permeability, repurposing

DOI: 10.3233/JAD-151179

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1499-1516, 2016

Authors: Grossi, Enzo | Stoccoro, Andrea | Tannorella, Pierpaola | Migliore, Lucia | Coppedè, Fabio

Article Type: Research Article

Abstract: Background: There is increasing interest in DNA methylation studies in Alzheimer’s disease (AD), but little is still known concerning the relationship between gene-promoter methylation and circulating biomarkers of one-carbon metabolism in patients. Objective: To detect the connections among circulating folate, homocysteine (hcy) and vitamin B12 levels and promoter methylation levels of PSEN1 , BACE1 , DNMT1 , DNMT3A , DNMT3B , and MTHFR genes in blood DNA. Methods: We applied a data mining system called Auto Contractive Map to an existing database of 100 AD and 100 control individuals. Results: Low vitamin …B12 was linked to the AD condition, to low folates, and to high hcy. Low PSEN1 methylation was linked to low folate levels as well as to low promoter methylation of BACE1 and DNMTs genes. Low hcy was linked to controls, to high folates and vitamin B12, as well as to high methylation levels of most of the studied genes. Conclusions: The present pilot study suggests that promoter methylation levels of the studied genes are linked to circulating levels of folates, hcy, and vitamin B12. Show more

Keywords: Alzheimer’s disease, BACE1, DNA methylation, DNMT, folate, homocysteine, MTHFR, PSEN1, vitamin B12

DOI: 10.3233/JAD-160210

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1517-1522, 2016

Authors: De Vos, Ann | Struyfs, Hanne | Jacobs, Dirk | Fransen, Erik | Klewansky, Tom | De Roeck, Ellen | Robberecht, Caroline | Van Broeckhoven, Christine | Duyckaerts, Charles | Engelborghs, Sebastiaan | Vanmechelen, Eugeen

Article Type: Research Article

Abstract: Background: In diagnosing Alzheimer’s disease (AD), ratios of cerebrospinal fluid (CSF) biomarkers, such as CSF Aβ1-42 /tau, have an improved diagnostic performance compared to the single analytes, yet, still a limited value to predict cognitive decline. Since synaptic dysfunction/loss is closely linked to cognitive impairment, synaptic proteins are investigated as candidate CSF AD progression markers. Objective: We studied CSF levels of the postsynaptic protein neurogranin and protein BACE1, predominantly localized presynaptically, and their relation to CSF total-tau, Aβ1-42 , Aβ1-40 , and Aβ1-38 . All six analytes were considered as single parameters as well as ratios. …Methods: Every ELISA involved was based on monoclonal antibodies, including the BACE1 and neurogranin immunoassay. The latter specifically targets neurogranin C-terminally truncated at P75, a more abundant species of the protein in CSF. We studied patients with MCI due to AD (n  = 38) and 50 dementia due to AD patients, as well as age-matched cognitively healthy elderly (n  = 20). A significant subset of the patients was followed up by clinical and neuropsychologically (MMSE) examinations for at least one year. Results: The single analytes showed statistically significant differences between the clinical groups, but the ratios of analytes indeed had a higher diagnostic performance. Furthermore, only the ratio of CSF neurogranin trunc P75/BACE1 was significantly correlated with the yearly decline in MMSE scores in patients with MCI and dementia due to AD, pointing toward the prognostic value of the ratio. Conclusion: This is the first study demonstrating that the CSF neurogranin trunc P75/BACE1 ratio, reflecting postsynaptic/presynaptic integrity, is related to cognitive decline. Show more

Keywords: Alzheimer’s disease, BACE1 protein, biomarkers, cerebrospinal fluid, ELISA, mild cognitive impairment, neurogranin, prognostic, ratio

DOI: 10.3233/JAD-160227

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1523-1538, 2016

Authors: Han, Bing | Yu, Lulu | Geng, Yuan | Shen, Li | Wang, Hualong | Wang, Yanyong | Wang, Jinhua | Wang, Mingwei

Article Type: Research Article

Abstract: Differences in brain function are a central determinant of individual variability in the stress response. Brain dysfunction, resulting from aging, illness, or genetic mutations, could reduce the tolerance of glucocorticoid stress hormones. When glucocorticoids exceed tolerable limits in the brain, especially in the hippocampus, this state can cause or aggravate structural or functional damage. However, the underlying mechanisms are not well understood. This study investigated the effects of chronic unpredictable mild stress (CUMS) in APP/PS1 and control mice. We showed that 4 weeks of CUMS exposure increased the levels of glucocorticoids, reduced glucocorticoids receptor expression, and promoted senile plaque deposition, …neuronal injury, and cognitive impairment in APP/PS1 mice compared to controls. The phosphorylation of insulin receptor, insulin receptor substrate 1 and associated signaling pathways (Akt, mTOR, p70S6K, ERK1/2, and PTEN) were decreased in hippocampus in APP/PS1 mice compared to control mice, while no changes were found in GSK3 and TSC2 phosphorylation. Furthermore, insulin and Akt/mTOR signaling pathways were further decreased in APP/PS1 mice after CUMS, which may be related to the activation of the stress-activated protein kinase JNK, while no alterations in the levels of phosphorylated ERK1/2, GSK3, PTEN, or TSC2 were observed. These results suggest that chronic stress may affect the insulin and Akt/mTOR pathway, accelerating the progression of Alzheimer’s disease in vulnerable individuals. Show more

Keywords: Alzheimer’s disease, cognitive function, hippocampus, insulin sensitivity, stress, transgenic animals

DOI: 10.3233/JAD-160189

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1539-1552, 2016

Authors: Bangen, Katherine J. | Himali, Jayandra J. | Beiser, Alexa S. | Nation, Daniel A. | Libon, David J. | Fox, Caroline S. | Seshadri, Sudha | Wolf, Philip A. | McKee, Ann C. | Au, Rhoda | Delano-Wood, Lisa

Article Type: Research Article

Abstract: Elevated blood glucose and the apolipoprotein (APOE) ɛ 4 allele have both been associated with increased dementia risk; however, the neuropathological mechanisms underlying these associations remain unclear. We examined the impact of APOE genotype and midlife blood glucose on post-mortem vascular and Alzheimer’s disease (AD) neuropathology. Ninety-four participants from the Framingham Heart Study without diagnosed diabetes underwent health examination at midlife and brain autopsy at death. Histopathological measures of vascular and AD neuropathology were obtained and analyzed. Results demonstrated that, among APOE ɛ 4 carriers, elevated blood glucose was associated with more severe AD pathology. There was no such relationship …with vascular pathology. In a relatively healthy sample with low vascular risk burden, midlife elevated blood glucose was associated with greater AD pathology among APOE ɛ 4 carriers. A better understanding of interactive effects of APOE genotype and vascular risk on neuropathology has implications for identification of individuals at risk for decline and long-term preventive treatment. Show more

Keywords: Alzheimer’s disease, apolipoprotein E (APOE), diabetes, glucose, neuropathology, vascular risk

DOI: 10.3233/JAD-160163

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1553-1562, 2016

Authors: Kang, Seokjo | Jeong, Hyobin | Baek, Je-Hyun | Lee, Seung-Jin | Han, Sun-Ho | Cho, Hyun Jin | Kim, Hee | Hong, Hyun Seok | Kim, Young Ho | Yi, Eugene C. | Seo, Sang Won | Na, Duk L. | Hwang, Daehee | Mook-Jung, Inhee

Article Type: Research Article

Abstract: Development of a simple, non-invasive early diagnosis platform of Alzheimer’s disease (AD) using blood is urgently required. Recently, PiB-PET imaging has been shown to be powerful to quantify amyloid-β plaque loads leading to pathophysiological alterations in AD brains. Thus, there has been a need for serum biomarkers reflecting PiB-PET imaging data as an early diagnosis platform of AD. Here, using LC-MS/MS analysis coupled with isobaric tagging, we performed comprehensive proteome profiling of serum samples from cognitively normal controls, mild cognitive impairment (MCI), and AD patients, who were selected using PiB-PET imaging. Comparative analysis of the proteomes revealed 79 and 72 …differentially expressed proteins in MCI and AD, respectively, compared to controls. Integrated analysis of these proteins with genomic and proteomic data of AD brain tissues, together with network analysis, identified three biomarker candidates representing the altered proteolysis-related process in MCI or AD: proprotein convertase subtilisin/kexin type 9 (PCSK9), coagulation factor XIII, A1 polypeptide (F13A1), and dermcidin (DCD). In independent serum samples of MCI and AD, we confirmed the elevation of the candidates using western blotting and ELISA. Our results suggest that these biomarker candidates can serve as a potential non-invasive early diagnosis platform reflecting PiB-PET imaging for MCI and AD. Show more

Keywords: Alzheimer’s disease, biomarker, LC-MS/MS, mild cognitive impairment, proteomics, serum

DOI: 10.3233/JAD-160025

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1563-1576, 2016

Authors: Li, Xudong | Jia, Shuhong | Zhou, Zhi | Hou, Chunlei | Zheng, Wenjing | Rong, Pei | Jiao, Jinsong

Article Type: Research Article

Abstract: Background: Alzheimer’s disease dementia (ADD) has become an important health problem in the world. Visuospatial deficits are considered to be an early symptom besides memory disorder. Objectives: The gesture imitation test was devised to detect ADD and amnestic mild cognitive impairment (aMCI). Methods: A total of 117 patients with ADD, 118 with aMCI, and 95 normal controls were included in this study. All participants were administered our gesture imitation test, the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Clock Drawing Test (CDT), and the Clinical Dementia Rating Scale (CDR). Results: …Patients with ADD performed worse than normal controls on global scores and had a lower success rate on every item (p  < 0.001). The area under the curve (AUC) for the global scores when comparing the ADD and control groups was 0.869 (p  < 0.001). Item 4 was a better discriminator with a sensitivity of 84.62% and a specificity of 67.37%. The AUC for the global scores decreased to 0.621 when applied to the aMCI and control groups (p  = 0.002). After controlling for age and education, the gesture imitation test scores were positively correlated with the MMSE (r  = 0.637, p  < 0.001), the MoCA (r  = 0.572, p  < 0.001), and the CDT (r  = 0.514, p  < 0.001) and were negatively correlated with the CDR scores (r  = –0.558, p  < 0.001). Conclusions: The gesture imitation test is an easy, rapid tool for detecting ADD, and is suitable for the patients suspected of mild ADD and aMCI in outpatient clinics. Show more

Keywords: Alzheimer’s disease, gesture imitation, mild cognitive impairment, neuropsychological test

DOI: 10.3233/JAD-160218

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1577-1584, 2016

Authors: Mowrey, Wenzhu B. | Lipton, Richard B. | Katz, Mindy J. | Ramratan, Wendy S. | Loewenstein, David A. | Zimmerman, Molly E. | Buschke, Herman

Article Type: Research Article

Abstract: Background: The Memory Binding Test (MBT), previously known as Memory Capacity Test, has demonstrated discriminative validity for distinguishing persons with amnestic mild cognitive impairment (aMCI) and dementia from cognitively normal elderly. Objective: We aimed to assess the predictive validity of the MBT for incident aMCI. Methods: In a longitudinal, community-based study of adults aged 70+, we administered the MBT to 246 cognitively normal elderly adults at baseline and followed them annually. Based on previous work, a subtle reduction in memory binding at baseline was defined by a Total Items in the Paired (TIP) condition score …of ≤22 on the MBT. Cox proportional hazards models were used to assess the predictive validity of the MBT for incident aMCI accounting for the effects of covariates. The hazard ratio of incident aMCI was also assessed for different prediction time windows ranging from 4 to 7 years of follow-up, separately. Results: Among 246 controls who were cognitively normal at baseline, 48 developed incident aMCI during follow-up. A baseline MBT reduction was associated with an increased risk for developing incident aMCI (hazard ratio (HR) = 2.44, 95% confidence interval: 1.30–4.56, p  = 0.005). When varying the prediction window from 4–7 years, the MBT reduction remained significant for predicting incident aMCI (HR range: 2.33–3.12, p : 0.0007–0.04). Conclusion: Persons with poor performance on the MBT are at significantly greater risk for developing incident aMCI. High hazard ratios up to seven years of follow-up suggest that the MBT is sensitive to early disease. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, longitudinal studies, memory, mild cognitive impairment, preclinical, survival analysis

DOI: 10.3233/JAD-160291

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1585-1595, 2016

Authors: Camargo, Erica C. | Weinstein, Galit | Beiser, Alexa S. | Tan, Zaldy S. | DeCarli, Charles | Kelly-Hayes, Margaret | Kase, Carlos | Murabito, Joanne M. | Seshadri, Sudha

Article Type: Research Article

Abstract: Background: Handgrip strength and gait speed are simple measures of physical capability and have been associated with current and future health outcomes. However, studies on their associations with brain structure and function in middle-aged adults are lacking. Objective: To assess the relationship of fast-paced walking speed and handgrip strength with risk of dementia, Alzheimer’s disease (AD), and stroke, as well as the cross-sectional associations with cognitive and brain magnetic resonance imaging (MRI) measures in a middle-aged community sample. Methods: Framingham Offspring (n  = 2,176; mean age 62, 54% female) had physical function, brain MRI, and cognitive …evaluations between 1999 and 2005 and were followed-up for incident dementia AD and stroke until 11 years later. We related walking speed and handgrip strength to incident dementia, AD, and stroke using Cox models, and to brain and cognitive measures using multivariable linear and logistic regression. Models were adjusted for age, sex, education, and vascular risk factors. Results: Slow walking and weak handgrip were associated with more than 2.5-fold increase in risk of AD. Weaker handgrip was associated with an increased risk of incident stroke (HR 1.74, 95% CI: 1.12–2.70/SDU, p  = 0.01) in persons ≥65 years. Both measures were associated with lower total brain volume and poorer performance on tests of visual memory, language, executive function, and visuoperceptual function. Slower gait was also related to poorer verbal memory, and weaker handgrip to poorer abstraction. Conclusion: Tests of walking speed and handgrip strength may serve as clinical markers of brain structure and function and may improve dementia risk prediction. Show more

Keywords: Alzheimer’s disease, brain imaging, cognitive function, dementia, gait, hand strength, observational study, stroke

DOI: 10.3233/JAD-160229

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1597-1608, 2016

Authors: Krell-Roesch, Janina | Ruider, Hanna | Lowe, Val J. | Stokin, Gorazd B. | Pink, Anna | Roberts, Rosebud O. | Mielke, Michelle M. | Knopman, David S. | Christianson, Teresa J. | Machulda, Mary M. | Jack, Clifford R. | Petersen, Ronald C. | Geda, Yonas E.

Article Type: Research Article

Abstract: One of the key research agenda of the field of aging is investigation of presymptomatic Alzheimer’s disease (AD). Furthermore, abnormalities in brain glucose metabolism (as measured by FDG-PET) have been reported among cognitively normal elderly persons. However, little is known about the association of FDG-PET abnormalities with neuropsychiatric symptoms (NPS) in a population-based setting. Thus, we conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging in order to examine the association between brain glucose metabolism and NPS among cognitively normal (CN) persons aged > 70 years. Participants underwent FDG-PET and completed the Neuropsychiatric Inventory Questionnaire (NPI-Q), Beck …Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). Cognitive classification was made by an expert consensus panel. We conducted multivariable logistic regression analyses to compute odds ratios (OR) and 95% confidence intervals after adjusting for age, sex, and education. For continuous variables, we used linear regression and Spearman rank-order correlations. Of 668 CN participants (median 78.1 years, 55.4% males), 205 had an abnormal FDG-PET (i.e., standardized uptake value ratio < 1.32 in AD-related regions). Abnormal FDG-PET was associated with depression as measured by NPI-Q (OR = 2.12; 1.23–3.64); the point estimate was further elevated for APOE ɛ 4 carriers (OR = 2.59; 1.00–6.69), though marginally significant. Additionally, we observed a significant association between abnormal FDG-PET and depressive and anxiety symptoms when treated as continuous measures. These findings indicate that NPS, even in community-based samples, can be an important additional tool to the biomarker-based investigation of presymptomatic AD. Show more

Keywords: Agitation, Alzheimer’s disease, anxiety, apathy, cognitively normal persons, depression, FDG-PET, neuroimaging, neuropsychiatric symptoms

DOI: 10.3233/JAD-160326

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1609-1616, 2016

Authors: Jakobsen, Jannik E. | Johansen, Marianne G. | Schmidt, Mette | Liu, Ying | Li, Rong | Callesen, Henrik | Melnikova, Margarita | Habekost, Mette | Matrone, Carmela | Bouter, Yvonne | Bayer, Thomas A. | Nielsen, Anders Lade | Duthie, Monika | Fraser, Paul E. | Holm, Ida E. | Jørgensen, Arne Lund

Article Type: Research Article

Abstract: Mutations in the amyloid-β protein precursor gene (AβPP ), the presenilin 1 gene (PSEN1 ) or the presenilin 2 gene (PSEN2 ) that increase production of the AβPP-derived peptide Aβ42 cause early-onset Alzheimer’s disease. Rodent models of the disease show that further increase in Aβ42 production and earlier brain pathology can be obtained by coexpressing AβPP and PSEN1 mutations. To generate such elevated Aβ42 level in a large animal model, we produced Göttingen minipigs carrying in their genome one copy of a human PSEN1 cDNA with the Met146Ile (PSEN1M146I ) mutation and three copies …of a human AβPP695 cDNA with the Lys670Asn/Met671Leu (AβPPsw ) double-mutation. Both transgenes were expressed in fibroblasts and in the brain, and their respective proteins were processed normally. Immunohistochemical staining with Aβ42 -specific antibodies detected intraneuronal accumulation of Aβ42 in brains from a 10- and an 18-month-old pig. Such accumulation may represent an early event in the pathogenesis of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid, porcine model, presenilin, transgenic

DOI: 10.3233/JAD-160408

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1617-1630, 2016

Authors: Venturelli, Massimo | Sollima, Alessio | Cè, Emiliano | Limonta, Eloisa | Bisconti, Angela V. | Brasioli, Anna | Muti, Ettore | Esposito, Fabio

Article Type: Research Article

Abstract: Sundowning syndrome (SDS) in patients with Alzheimer’s disease (AD) is characterized by the intensification of behavioral disorders at sunset. Despite SDS etiology being unclear, a strong relationship between high cortisol levels and SDS has been reported. Aerobic exercise (AE) and cognitive training (CT) can reduce cortisol levels. However, whether SDS would benefit from AE and CT is still unknown. Therefore, the aim of this study was to investigate whether AE and CT treatments are effective in reducing SDS via downregulation of cortisol levels. The possible additive effects of combined AE+CT were also assessed. Eighty AD patients were randomly assigned to …AE (n  = 20), CT (n  = 20), AE+CT (n  = 20), and standard therapy (no treatment, NT; n  = 20). Treatments were administered for 3 months, 5 days/week, 1 hour before sunset. Before and after treatments, salivary cortisol levels were sampled at 7, 11, 15, at sunset, and 20 (time of day). Blind assessment of behavioral disorders (neuropsychiatric inventory, NPI) and agitation (agitated behavior scale, ABS) were also performed. After interventions, cortisol levels were reduced in AE and AE+CT by ∼26%. In the same groups, NPI and ABS decreased by ∼50%. By contrast, cortisol and behavioral disorders were similar to baseline in CT and NT. Changes in NPI and ABS were significantly correlated with the reduction in cortisol levels. AE or AE+CT effects on SDS and cortisol levels and the lack of effect of CT alone indicate the effectiveness of an exercise-based treatment on SDS, suggesting a possible hypothalamic–pituitary–adrenal axis dysregulation underpinning SDS. Show more

Keywords: Alzheimer’s disease, behavioral disorders, cortisol, exercise

DOI: 10.3233/JAD-160392

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1631-1640, 2016

Authors: Malek-Ahmadi, Michael | Perez, Sylvia E. | Chen, Kewei | Mufson, Elliott J.

Article Type: Research Article

Abstract: The presence of Alzheimer’s disease (AD)-related neuropathology among cognitively normal individuals has been well documented. It has been proposed that these individuals may represent a pre-clinical AD population. Previous studies have demonstrated a negative association between the presence of both amyloid-β (Aβ) plaques and neurofibrillary tangles with ante-mortem cognitive performance, a relationship which is likely influenced by a number of factors including age and APOE ɛ 4 carrier status. The present study determined whether the presence of neuritic plaques (NPs) and diffuse plaques (DPs) are associated with performance in a number of cognitive domains after accounting for APOE ɛ 4 …carrier status and neurofibrillary tangle presence in a cohort of 123 older participants from the Rush Religious Order Study who died with a premortem clinical diagnosis of no cognitive impairment (NCI). After adjusting for age at death, education, gender, Braak stage, and APOE ɛ 4 carrier status, the presence of NPs was associated with lower performance in the cognitive domains of Global Cognition (p  = 0.002), Episodic Memory (p  = 0.03), Semantic Memory (p  = 0.009), and Visuospatial performance (p  = 0.006), while DPs showed no association with any cognitive domain examined. These results suggest that decreases in cognition in elderly NCI individuals are associated with an increase in NPs and not DPs when age at death, education, gender, APOE ɛ 4 status, and Braak stage are taken into consideration. Show more

Keywords: Amyloid-β, Braak stage, cognition, neuropathology, pre-clinical Alzheimer’s disease

DOI: 10.3233/JAD-160365

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1641-1652, 2016

Article Type: Other

DOI: 10.3233/JAD-160628

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1653-1657, 2016

Article Type: Other

Citation: Journal of Alzheimer's Disease, vol. 53, no. 4, pp. 1659-1675, 2016