Journal of Alzheimer's Disease - Volume 51, issue 4

Authors: Yao, Qian | Jiang, Guo-Xin | Zhou, Zhi-Ming | Chen, Jin-Mei | Cheng, Qi

Article Type: Research Article

Abstract: Background: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI). Objective: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly. Methods: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current …drinking, and physical activities. Results: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR = 2.277; 95% CI: 1.086–4.773). Among MetS components, abdominal obesity (OR = 2.101; 95% CI: 1.224–3.608) and hypertension (OR = 2.075; 95% CI: 1.170–3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR = 2.459; 95% CI: 1.360–4.447). Conclusion: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI. Show more

Keywords: Abdominal obesity, case-control study, hypertension, metabolic syndrome, mild cognitive impairment

DOI: 10.3233/JAD-150920

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1175-1182, 2016

Authors: Ongali, Brice | Nicolakakis, Nektaria | Tong, Xing-Kang | Aboulkassim, Tahar | Imboden, Hans | Hamel, Edith

Article Type: Research Article

Abstract: The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer’s disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (∼15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase …subunit p67phox ), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1 - 42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate antihypertensive therapy in AD patients. Show more

Keywords: Alzheimer’s disease, angiotensin II, angiotensin converting enzyme inhibitors (ACEi), APP mice, enalapril, losartan

DOI: 10.3233/JAD-150868

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1183-1195, 2016

Authors: Son, Sung Min | Shin, Hong-Joon | Byun, Jayoung | Kook, Sun Young | Moon, Minho | Chang, Yu Jin | Mook-Jung, Inhee

Article Type: Research Article

Abstract: The evidence of strong pathological associations between type 2 diabetes and Alzheimer’s disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage® ) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ -secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ -secretase activity was also detected in autophagic vacuoles, apparently a novel …site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ -secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes. Show more

Keywords: Alzheimer’s disease, amyloid-β peptides, amyloid-β protein precursor, autophagy, metformin

DOI: 10.3233/JAD-151200

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1197-1208, 2016

Authors: Elahi, Montasir | Hasan, Zafrul | Motoi, Yumiko | Matsumoto, Shin-Ei | Ishiguro, Koichi | Hattori, Nobutaka

Article Type: Research Article

Abstract: Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer’s disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability …or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 to 18 months old) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD. Show more

Keywords: Alzheimer’s disease, cytokines, diabetes mellitus, microglia, neuroinflammation, oxidative stress, tauopathy

DOI: 10.3233/JAD-150820

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1209-1224, 2016

Authors: Lavallée, Marie Maxime | Gandini, Delphine | Rouleau, Isabelle | Vallet, Guillaume T. | Joannette, Maude | Kergoat, Marie-Jeanne | Busigny, Thomas | Rossion, Bruno | Joubert, Sven

Article Type: Research Article

Abstract: Prevalent face recognition difficulties in Alzheimer’s disease (AD) have typically been attributed to the underlying episodic and semantic memory impairment. The aim of the current study was to determine if AD patients are also impaired at the perceptual level for faces, more specifically at extracting a visual representation of an individual face. To address this question, we investigated the matching of simultaneously presented individual faces and of other nonface familiar shapes (cars), at both upright and inverted orientation, in a group of mild AD patients and in a group of healthy older controls matched for age and education. AD patients …showed a reduced inversion effect (i.e., larger performance for upright than inverted stimuli) for faces, but not for cars, both in terms of error rates and response times. While healthy participants showed a much larger decrease in performance for faces than for cars with inversion, the inversion effect did not differ significantly for faces and cars in AD. This abnormal inversion effect for faces was observed in a large subset of individual patients with AD. These results suggest that AD patients have deficits in higher-level visual processes, more specifically at perceiving individual faces, a function that relies on holistic representations specific to upright face stimuli. These deficits, combined with their memory impairment, may contribute to the difficulties in recognizing familiar people that are often reported in patients suffering from the disease and by their caregivers. Show more

Keywords: Alzheimer’s disease, face inversion effect, face recognition, vision, visuoperceptual processing

DOI: 10.3233/JAD-151027

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1225-1236, 2016

Authors: Florian, Hana | Meier, Andreas | Gauthier, Serge | Lipschitz, Stanley | Lin, Yunzhi | Tang, Qi | Othman, Ahmed A. | Robieson, Weining Z. | Gault, Laura M.

Article Type: Research Article

Abstract: Background: ABT-126 is a potent, selective α 7 nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer’s disease (AD). Objective: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT-126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs). Methods: Subjects received 25 mg ABT-126 (n  = 143), 75 mg ABT-126 (n  = 145), or placebo (n  = 146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28-week open-label extension study (NCT01690195) and received 75 mg ABT-126 daily. …The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog). Results: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT-126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, –1.21; standard error, 0.51; p  <  0.010, one-sided); 75 mg ABT-126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT-126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache. Conclusions: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD. Show more

Keywords: ABT-126, Acetylcholinesterase inhibitors, alzheimer’s disease, dementia, nicotinic acetylcholine receptors

DOI: 10.3233/JAD-150978

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1237-1247, 2016

Authors: Gossink, Flora T. | Dols, Annemieke | Krudop, Welmoed A. | Sikkes, Sietske A. | Kerssens, Cora J. | Prins, Niels D. | Scheltens, Philip | Stek, Max L. | Pijnenburg, Yolande A.L.

Article Type: Research Article

Abstract: While psychiatric misdiagnosis is well-known in behavioral variant frontotemporal dementia (bvFTD), a systematic evaluation of standardized criteria for psychiatric disorders in bvFTD is still missing. Our aim was to define frequency and character of DSM-IV psychiatric disorders among patients with probable and definite bvFTD compared to possible bvFTD, other neurodegenerative diseases, and psychiatric diagnoses, using MINI-International Neuropsychiatric Interview. We additionally compared psychiatric prodromes between these groups. Subjects were participants of the late-onset frontal lobe (LOF) study, a longitudinal multicenter study. In each patient, after baseline diagnostic procedure, a neurologist and geriatric psychiatrist made a joint clinical diagnosis. Independently, a structured …diagnostic interview according to DSM-IV and ICD-10 criteria (MINI-Plus) was performed by a trained professional blinded to clinical diagnosis. Out of 91 patients, 23 with probable and definite bvFTD, 3 with possible bvFTD, 25 with a non bvFTD neurodegenerative disease, and 40 with a clinical psychiatric diagnosis were included. Overall frequency of formal current and past psychiatric disorders in probable and definite bvFTD (21.7% current, 8.7% past) did not differ from other neurodegenerative diseases (12.0% current, 16.0% past) or possible bvFTD (66.7% current, 66.7% past), but was less than in patients with a clinical psychiatric diagnosis (57.5% current, 62.5% past; p  <  0.01). In probable and definite bvFTD unipolar mood disorders were most common. Formally diagnosed psychiatric disorders are not overrepresented in probable bvFTD, suggesting that psychiatric misdiagnosis in bvFTD can be reduced by strictly applying diagnostic criteria. In suspected bvFTD close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment. Show more

Keywords: Behavior, behavioral variant frontotemporal dementia, DSMIV criteria, ICD-10 criteria, misdiagnosis, neurology, psychiatric disorders, psychiatry

DOI: 10.3233/JAD-151198

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1249-1256, 2016

Authors: Masoud, Anwar M. | Bihaqi, Syed W. | Machan, Jason T. | Zawia, Nasser H. | Renehan, William E.

Article Type: Research Article

Abstract: There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function, and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 h after birth) to PND 20 via their …mother’s milk. Brain tissue was harvested at PND 20, 180, or 700, and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR-29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins. Show more

Keywords: Amyloid-β protein precursor, lead, miRNA, neurodegeneration, tau

DOI: 10.3233/JAD-151018

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1257-1264, 2016

Authors: Montesanto, Alberto | Crocco, Paolina | Anfossi, Maria | Smirne, Nicoletta | Puccio, Gianfranco | Colao, Rosanna | Maletta, Raffaele | Passarino, Giuseppe | Bruni, Amalia C. | Rose, Giuseppina

Article Type: Research Article

Abstract: Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer’s disease (AD) patients. Here we analyzed the variability of UCP2 , -3 , -4 , and 5 …genes in sporadic and familial cases (n  = 465) of late-onset AD (LOAD) with respect to healthy controls (n  = 442). We showed that a genetic variant in the human UCP4 , rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE -ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p  = 6.934* 10–4 for familial and p  = 1.033* 10–3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ 4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ɛ 4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis. Show more

Keywords: Alzheimer’s disease, APOE, genetic risk, mitochondria, neurodegeneration, UCP4, uncoupling proteins

DOI: 10.3233/JAD-150993

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1265-1274, 2016

Authors: Femminella, Grazia D. | Ninan, Siddharth | Atkinson, Rebecca | Fan, Zhen | Brooks, David J. | Edison, Paul

Article Type: Research Article

Abstract: Background: The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) is still unclear. Objectives: Here we investigated whether microglial activation measured by [11 C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements. Methods: We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11 C](R)PK11195, [18 F]FDG, and volumetric MRI scanning. Results: SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and …microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD. Conclusions: These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases. Show more

Keywords: Alzheimer’s disease, neuroinflammation, Parkinson’s disease with dementia, PET, volumetric MRI

DOI: 10.3233/JAD-150827

Citation: Journal of Alzheimer's Disease, vol. 51, no. 4, pp. 1275-1289, 2016