Journal of Alzheimer's Disease - Volume 50, issue 2

Authors: Gardener, Samantha L. | Rainey-Smith, Stephanie R. | Martins, Ralph N.

Article Type: Review Article

Abstract: Inflammation is one of the pathological features of the neurodegenerative disease, Alzheimer’s disease (AD). A number of additional disorders are likewise associated with a state of chronic inflammation, including obesity, cardiovascular disease, and type-2 diabetes, which are themselves risk factors for AD. Dietary components have been shown to modify the inflammatory process at several steps of the inflammatory pathway. This review aims to evaluate the published literature on the effect of consumption of pro- or anti-inflammatory dietary constituents on the severity of both AD pathology and related chronic diseases, concentrating on the dietary constituents of flavonoids, spices, and fats. Diet-based …anti-inflammatory components could lead to the development of potent novel anti-inflammatory compounds for a range of diseases. However, further work is required to fully characterize the therapeutic potential of such compounds, including gaining an understanding of dose-dependent relationships and limiting factors to effectiveness. Nutritional interventions utilizing anti-inflammatory foods may prove to be a valuable asset in not only delaying or preventing the development of age-related neurodegenerative diseases such as AD, but also treating pre-existing conditions including type-2 diabetes, cardiovascular disease, and obesity. Show more

Keywords: Alzheimer’s disease, cardiovascular disease, curcumin, diabetes, diet, docosahexaenoic acid, eicosapentaenoic acid, flavonoids, inflammation, obesity

DOI: 10.3233/JAD-150765

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 301-334, 2016

Authors: Chakrabarti, Mrinmay | McDonald, Alexander J. | Will Reed, J. | Moss, Melissa A. | Das, Bhaskar C. | Ray, Swapan K.

Article Type: Review Article

Abstract: Retinoids, which are vitamin A derivatives, interact through retinoic acid receptors (RARs) and retinoid X receptors (RXRs) and have profound effects on several physiological and pathological processes in the brain. The presence of retinoic acid signaling is extensively detected in the adult central nervous system, including the amygdala, cortex, hypothalamus, hippocampus, and other brain areas. Retinoids are primarily involved in neural patterning, differentiation, and axon outgrowth. Retinoids also play a key role in the preservation of the differentiated state of adult neurons. Impairment in retinoic acid signaling can result in neurodegeneration and progression of Alzheimer’s disease (AD). Recent studies demonstrated …severe deficiencies in spatial learning and memory in mice during retinoic acid (vitamin A) deprivation indicating its significance in preserving memory function. Defective cholinergic neurotransmission plays an important role in cognitive deficits in AD. All-trans retinoic acid is known to enhance the expression and activity of choline acetyltransferase in neuronal cell lines. Activation of RAR and RXR is also known to impede the pathogenesis of AD in mice by inhibiting accumulation of amyloids. In addition, retinoids have been shown to inhibit the expression of chemokines and pro-inflammatory cytokines in microglia and astrocytes, which are activated in AD. In this review article, we have described the chemistry and molecular signaling mechanisms of natural and synthetic retinoids and current understandings of their therapeutic potentials in prevention of AD pathology. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuroprotection, regenerative medicine, retinoids

DOI: 10.3233/JAD-150450

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 335-352, 2016

Authors: Oldoni, Emanuela | Fumagalli, Giorgio G. | Serpente, Maria | Fenoglio, Chiara | Scarioni, Marta | Arighi, Andrea | Bruno, Giuseppe | Talarico, Giuseppina | Confaloni, Annamaria | Piscopo, Paola | Nacmias, Benedetta | Sorbi, Sandro | Rainero, Innocenzo | Rubino, Elisa | Pinessi, Lorenzo | Binetti, Giuliano | Ghidoni, Roberta | Benussi, Luisa | Grande, Giulia | Arosio, Beatrice | Bursey, Devan | Kauwe, John S. | Cioffi, Sara MG | Arcaro, Marina | Mari, Daniela | Mariani, Claudio | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: The missense P39L variant in the prion protein gene (PRNP ) has recently been associated with frontotemporal dementia (FTD). Here, we analyzed the presence of the P39L variant in 761 patients with FTD and 719 controls and found a single carrier among patients. The patient was a 67-year-old male, with a positive family history for dementia, who developed apathy, short term memory deficit, and postural instability at 66. Clinical and instrumental workup excluded prion disease. At MRI, bilateral frontal lobe atrophy was present. A diagnosis of FTD was made, with a mainly apathetic phenotype. The PRNP P39L mutation may …be an extremely rare cause of FTD (0.13%). Show more

Keywords: Frontotemporal dementia, mutation, P39L, prion, PRNP

DOI: 10.3233/JAD-150863

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 353-357, 2016

Authors: Hardy, Chris J.D. | Buckley, Aisling H. | Downey, Laura E. | Lehmann, Manja | Zimmerer, Vitor C. | Varley, Rosemary A. | Crutch, Sebastian J. | Rohrer, Jonathan D. | Warrington, Elizabeth K. | Warren, Jason D.

Article Type: Research Article

Abstract: Background: The language profile of behavioral variant frontotemporal dementia (bvFTD) remains to be fully defined. Objective: We aimed to quantify the extent of language deficits in this patient group. Methods: We assessed a cohort of patients with bvFTD (n  = 24) in relation to patients with semantic variant primary progressive aphasia (svPPA; n  = 14), nonfluent variant primary progressive aphasia (nfvPPA; n  = 18), and healthy age-matched individuals (n  = 24) cross-sectionally and longitudinally using a comprehensive battery of language and general neuropsychological tests. Neuroanatomical associations of language performance were assessed using voxel-based morphometry of patients’ brain magnetic resonance images. …Results: Relative to healthy controls, and after accounting for nonverbal executive performance, patients with bvFTD showed deficits of noun and verb naming and single word comprehension, diminished spontaneous propositional speech, and deterioration in naming performance over time. Within the bvFTD group, patients with MAPT mutations had more severe impairments of noun naming and single word comprehension than patients with C9orf72 mutations. Overall the bvFTD group had less severe language deficits than patients with PPA, but showed a language profile that was qualitatively similar to svPPA. Neuroanatomical correlates of naming and word comprehension performance in bvFTD were identified predominantly in inferior frontal and antero-inferior temporal cortices within the dominant hemispheric language network. Conclusions: bvFTD is associated with a language profile including verbal semantic impairment that warrants further evaluation as a novel biomarker. Show more

Keywords: Behavioral variant frontotemporal dementia, frontotemporal dementia, primary progressive aphasia

DOI: 10.3233/JAD-150806

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 359-371, 2016

Authors: Deochand, Chetram | Tong, Ming | Agarwal, Amit R. | Cadenas, Enrique | de la Monte, Suzanne M.

Article Type: Research Article

Abstract: Background: Human studies suggest tobacco smoking is a risk factor for cognitive impairment and neurodegeneration, including Alzheimer’s disease (AD). However, experimental data linking tobacco smoke exposures to underlying mediators of neurodegeneration, including impairments in brain insulin and insulin-like growth factor (IGF) signaling in AD are lacking. Objective: This study tests the hypothesis that cigarette smoke (CS) exposures can impair brain insulin/IGF signaling and alter expression of AD-associated proteins. Methods: Adult male A/J mice were exposed to air for 8 weeks (A8), CS for 4 or 8 weeks (CS4, CS8), or CS8 followed by 2 weeks recovery …(CS8+R). Gene expression was measured by qRT-PCR analysis and proteins were measured by multiplex bead-based or direct binding duplex ELISAs. Results: CS exposure effects on insulin/IGF and insulin receptor substrate (IRS) proteins and phosphorylated proteins were striking compared with the mRNA. The main consequences of CS4 or CS8 exposures were to significantly reduce insulin R, IGF-1R, IRS-1, and tyrosine phosphorylated insulin R and IGF-1R proteins. Paradoxically, these effects were even greater in the CS8+R group. In addition, relative levels of S312 -IRS-1, which inhibits downstream signaling, were increased in the CS4, CS8, and CS8+R groups. Correspondingly, CS and CS8+R exposures inhibited expression of proteins and phosphoproteins required for signaling through Akt, PRAS40, and/or p70S6K, increased Aβ PP-Aβ , and reduced ASPH protein, which is a target of insulin/IGF-1 signaling. Conclusion: Secondhand CS exposures caused molecular and biochemical abnormalities in brain that overlap with the findings in AD, and many of these effects were sustained or worsened despite short-term CS withdrawal. Show more

Keywords: Alzheimer’s disease, cigarette smoke, insulin resistance, mouse model, neurodegeneration

DOI: 10.3233/JAD-150664

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 373-386, 2016

Authors: Wimo, Anders | Sjölund, Britt-Marie | Sköldunger, Anders | Qiu, Chengxuan | Klarin, Inga | Nordberg, Gunilla | von Strauss, Eva

Article Type: Research Article

Abstract: Background: Recent studies suggest that trends in cardiovascular risk may result in a decrease in age-specific prevalence of dementia. Studies in rural areas are rare. Objectives: To study cohort effects in dementia prevalence and survival of people with dementia in a Swedish rural area. Methods: Participants were from the 1995-1998 Nordanstig Project (NP) (n  = 303) and the 2001-2003 Swedish National study on Aging and Care in Nordanstig (SNAC-N) (n  = 384). Overall 6-year dementia prevalence and mortality in NP and SNAC-N were compared for people 78 years and older. Logistic regression analyses were used to calculate odds …ratios (ORs) and 95% confidence intervals (CIs) for dementia occurrence using the NP study population as the reference group. Cox regression models were used to analyze time to death. Results: The crude prevalence of dementia was 21.8% in NP and 17.4% in SNAC-N. When the NP cohort was used as the reference group, the age- and gender-adjusted OR of dementia was 0.71 (95% CI 0.48–1.04) in SNAC-N; the OR was 0.47 (0.24–0.90) for men and 0.88 (0.54–1.44) for women. In the extended model, the OR of dementia was significantly lower in SNAC-N than in the NP cohort as a whole (0.63; 0.39–0.99) and in men (0.34; 0.15–0.79), but not in women (0.81; 0.46–1.44). The Cox regression models indicated that the hazard ratio of dying was lower in the SNAC-N than NP population. Conclusions: Trends toward a lower prevalence of dementia in high-income countries seem to be evident in this Swedish rural area, at least in men. Show more

Keywords: Dementia, mortality, prevalence, rural population

DOI: 10.3233/JAD-150708

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 387-396, 2016

Authors: Weissmann, Robert | Hüttenrauch, Melanie | Kacprowski, Tim | Bouter, Yvonne | Pradier, Laurent | Bayer, Thomas A. | Kuss, Andreas W. | Wirths, Oliver

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by early intraneuronal amyloid-β (Aβ) accumulation, extracellular deposition of Aβ peptides, and intracellular hyperphosphorylated tau aggregates. These lesions cause dendritic and synaptic alterations and induce an inflammatory response in the diseased brain. Although the neuropathological characteristics of AD have been known for decades, the molecular mechanisms causing the disease are still under investigation. Studying gene expression changes in postmortem AD brain tissue can yield new insights into the molecular disease mechanisms. To that end, one can employ transgenic AD mouse models and the next-generation sequencing technology. In this study, a whole-brain …transcriptome analysis was carried out using the well-characterized APP/PS1KI mouse model for AD. These mice display a robust phenotype reflected by working memory deficits at 6 months of age, a significant neuron loss in a variety of brain areas including the CA1 region of the hippocampus and a severe amyloid pathology. Based on deep sequencing, differentially expressed genes (DEGs) between 6-month-old WT or PS1KI and APP/PS1KI were identified and verified by qRT-PCR. Compared to WT mice, 250 DEGs were found in APP/PS1KI mice, while 186 DEGs could be found compared to PS1KI control mice. Most of the DEGs were upregulated in APP/PS1KI mice and belong to either inflammation-associated pathways or lysosomal activation, which is likely due to the robust intraneuronal accumulation of Aβ in this mouse model. Our comprehensive brain transcriptome study further highlights APP/PS1KI mice as a valuable model for AD, covering molecular inflammatory and immune responses. Show more

Keywords: Alzheimer’s disease, amyloid, differential gene expression, next-generation sequencing, transcriptome, transgenic mice

DOI: 10.3233/JAD-150745

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 397-409, 2016

Authors: Chang, Yu-Ling | Yen, Yu-Shiuan | Chen, Ta-Fu | Yan, Sui-Hing | Tseng, Wen-Yih Isaac

Article Type: Research Article

Abstract: This study investigated the putative changes in regional gray matter and cingulum bundle segments in mild cognitive impairment (MCI) by using two diagnostic criteria. Participants comprised 50 older adults with MCI and 22 healthy older controls (HC). The older adults with MCI were further divided into two groups defined by a global Clinical Dementia Rating (CDR) score of 0.5 and with (the CDR/NPT MCI group) or without (the CDR MCI group) objective cognitive impairments determined using neuropsychological tests (NPTs). Comparable regional gray matter integrity was observed among the three groups. However, the integrity of the right inferior segment of the …cingulum bundle in the two MCI groups was more reduced than that in the HC group, and the CDR/NPT MCI group exhibited additional disruption in the left inferior cingulum bundle. The results also demonstrated that neuropsychological measures have greater predictive value for changes in white matter beyond the contribution of an informant-based instrument alone. Overall, the findings confirm the utility of informant-based assessment in detecting microstructural brain changes in high-risk older adults, even before objective cognitive impairment is evident. The findings also suggest that combining the neuropsychological measures with the informant-based assessment provided the greatest predictive value in assessing white matter disruption. The essential role of the white matter measurement as a biomarker for detecting individuals at a high risk of developing dementia was highlighted. Show more

Keywords: Alzheimer’s disease, cognition, diffusion magnetic resonance imaging, early diagnosis, mild cognitive impairment, neuropsychology

DOI: 10.3233/JAD-150599

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 411-423, 2016

Authors: Dermody, Nadene | Hornberger, Michael | Piguet, Olivier | Hodges, John R. | Irish, Muireann

Article Type: Research Article

Abstract: Background: Prospective memory (PM) refers to a future-oriented form of memory in which the individual must remember to execute an intended action either at a future point in time (Time-based) or in response to a specific event (Event-based). Lapses in PM are commonly exhibited in neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), however, the neurocognitive mechanisms driving these deficits remain unknown. Objective: To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). Methods: Twelve AD, 12 bvFTD, and 12 healthy older Control participants …completed a modified version of the Cambridge Prospective Memory test, which examines Time- and Event-based aspects of PM. All participants completed a standard neuropsychological assessment and underwent whole-brain structural MRI. Results: AD and bvFTD patients displayed striking impairments across Time- and Event-based PM relative to Controls, however, Time-based PM was disproportionately affected in the AD group. Episodic memory dysfunction and hippocampal atrophy were found to correlate strongly with PM integrity in both patient groups, however, dissociable neural substrates were also evident for PM performance across dementia syndromes. Conclusion: Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient’s daily life. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, episodic memory, frontal lobe, hippocampus, parietal lobe, prospective memory

DOI: 10.3233/JAD-150871

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 425-441, 2016

Authors: Hoffmann, Kristine | Sobol, Nanna A. | Frederiksen, Kristian S. | Beyer, Nina | Vogel, Asmus | Vestergaard, Karsten | Brændgaard, Hans | Gottrup, Hanne | Lolk, Annette | Wermuth, Lene | Jacobsen, Søren | Laugesen, Lars P. | Gergelyffy, Robert G. | Høgh, Peter | Bjerregaard, Eva | Andersen, Birgitte B. | Siersma, Volkert | Johannsen, Peter | Cotman, Carl W. | Waldemar, Gunhild | Hasselbalch, Steen G.

Article Type: Research Article

Abstract: Background: Studies of physical exercise in patients with Alzheimer’s disease (AD) are few and results have been inconsistent. Objective: To assess the effects of a moderate-to-high intensity aerobic exercise program in patients with mild AD. Methods: In a randomized controlled trial, we recruited 200 patients with mild AD to a supervised exercise group (60-min sessions three times a week for 16 weeks) or to a control group. Primary outcome was changed from baseline in cognitive performance estimated by Symbol Digit Modalities Test (SDMT) in the intention-to-treat (ITT) group. Secondary outcomes included changes in quality of life, …ability to perform activities of daily living, and in neuropsychiatric and depressive symptoms. Results: The ITT analysis showed no significant differences between intervention and control groups in change from baseline of SDMT, other cognitive tests, quality of life, or activities of daily living. The change from baseline in Neuropsychiatric Inventory differed significantly in favor of the intervention group (mean: –3.5, 95% confidence interval (CI) –5.8 to –1.3, p  = 0.002). In subjects who adhered to the protocol, we found a significant effect on change from baseline in SDMT as compared with the control group (mean: 4.2, 95% CI 0.5 to 7.9, p  = 0.028), suggesting a dose-response relationship between exercise and cognition. Conclusions: This is the first randomized controlled trial with supervised moderate-to-high intensity exercise in patients with mild AD. Exercise reduced neuropsychiatric symptoms in patients with mild AD, with possible additional benefits of preserved cognition in a subgroup of patients exercising with high attendance and intensity. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, cognition, exercise, randomized controlled trial

DOI: 10.3233/JAD-150817

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 443-453, 2016

Authors: Zhang, Ting | Li, He | Zhang, Junying | Li, Xin | Qi, Di | Wang, Nuo | Zhang, Zhanjun

Article Type: Research Article

Abstract: Epidemiological and clinical studies suggest that high serum cholesterol is a risk factor of dementia. However, the effects of cholesterol on cognition and brain remain largely unclear. This study aims to investigate the associations between serum total cholesterol (TC) and neuropsychological performance, and intrinsic functional networks in non-demented elderly. Among a cohort of 120 community-dwelling Beijing residents, 29 subjects in the high-TC group (1st quartile) and 31 in the low-TC group (4th quartile) were included in this study, and underwent a battery of neuropsychological tests and magnetic resonance imaging (MRI) scans, including T2- and T1-weighted imaging, and resting-state functional MRI. …No significant group difference was found in any of the neuropsychological tests used. Stronger connectivity in the default mode network was observed in the high-TC group compared to that in the low-TC group (p  <  0.001, uncorrected). While in the salience network (SN), the high-TC group showed lower connectivity in the anterior cingulate cortex and frontal regions, compared to the low-TC group (p  <  0.05, FWE corrected). Our findings suggest that in non-demented elderly persons, high serum cholesterol is associated with disruption of functional connectivity in the SN. The results not only deepen our understanding of how cholesterol affects the brain, but are also significant for selecting sensitive indicators for monitoring the impairments of cholesterol on the neural system. Show more

Keywords: Cognition, default mode network, functional connectivity, salience network, serum cholesterol

DOI: 10.3233/JAD-150810

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 455-463, 2016

Authors: Baiardi, Simone | Capellari, Sabina | Ladogana, Anna | Strumia, Silvia | Santangelo, Mario | Pocchiari, Maurizio | Parchi, Piero

Article Type: Research Article

Abstract: The Heidenhain variant defines a peculiar clinical presentation of sporadic Creutzfeldt-Jakob disease (sCJD) characterized by isolated visual disturbances at disease onset and reflecting the early targeting of prions to the occipital cortex. Molecular and histopathological typing, thus far performed in 23 cases, has linked the Heidenhain variant to the MM1 sCJD type. To contribute a comprehensive characterization of cases with the Heidenhain variant, we reviewed a series of 370 definite sCJD cases. Eighteen patients (4.9%) fulfilled the selection criteria. Fourteen of them belonging to sCJD types MM1 or MM1+2C had a short duration of isolated visual symptoms and overall clinical …disease, a high prevalence of periodic sharp-wave complexes in EEG, and a marked increase of cerebrospinal fluid proteins t-tau and 14-3-3 levels. In contrast, three cases of the MM 2C or MM 2+1C types showed a longer duration of isolated visual symptoms and overall clinical disease, non-specific EEG findings, and cerebrospinal fluid concentration below threshold for the diagnosis of “probable” CJD of both 14-3-3 and t-tau. However, a brain DWI-MRI disclosed an occipital cortical hyperintensity in the majority of examined cases of both groups. While confirming the strong linkage with the methionine genotype at the polymorphic codon 129 of the prion protein gene, our results definitely establish that the Heidenhain variant can also be associated with the MM 2C sCJD type in addition to the more common MM1 type. Likewise, our results highlight the significant differences in clinical evolution and laboratory findings between cases according to the dominant PrPSc type (type 1 versus type 2). Show more

Keywords: Dementia, molecular typing, neurodegenerative diseases, occipital cortex, prion diseases, prion protein

DOI: 10.3233/JAD-150668

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 465-476, 2016

Authors: Bartolotti, Nancy | Segura, Laura | Lazarov, Orly

Article Type: Research Article

Abstract: The mechanism underlying impaired learning and memory in Alzheimer’s disease is not fully elucidated. The phosphorylation of cyclic-AMP response element binding protein (pCREB) in the hippocampus is thought to be a critical initiating step in the formation of long-term memories. Here, we tested CRE-driven gene expression following learning in mice harboring the familial Alzheimer’s disease-linked APPswe/PS1ΔE9 mutations using CRE-β galactosidase reporter. We show that young adult APPswe/PS1ΔE9 mice exhibit impaired recognition memory and reduced levels of pCREB, and its cofactors CREB binding protein (CBP) and p-300 following a learning task, compared to their wild type littermate counterparts. Impairments in learning-induced …activation of CREB in these mice are manifested by reduced CRE-driven gene transcription. Importantly, expression of the CRE-driven immediate early gene, Egr-1 (Zif268) is decreased in the CA1 region of the hippocampus. These studies implicate defective CREB-dependent plasticity in the mechanism underlying learning and memory deficits in Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, CBP, CRE, CREB, hippocampal plasticity, learning and memory

DOI: 10.3233/JAD-150650

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 477-489, 2016

Authors: Sugiyama, Kemmyo | Tomata, Yasutake | Kaiho, Yu | Honkura, Kenji | Sugawara, Yumi | Tsuji, Ichiro

Article Type: Research Article

Abstract: Epidemiological studies of the association between coffee consumption and dementia have yielded inconsistent results. Therefore, we investigated the association between coffee consumption and incident risk of dementia in an elderly Japanese population. 23,091 subjects aged ≥65 y living in Ohsaki City, northeastern Japan, responded to the baseline survey in 2006. Of these, we analyzed 13,137 subjects who gave informed consent and were not disabled at baseline. The outcome was the incidence of disabling dementia defined by usage of the Long-term Care Insurance database. We used the Cox proportional hazards regression model for multivariate analysis. During 5.7 y of follow-up period, …we identified 1,107 cases of incident dementia. Overall, coffee consumption was significantly associated with a lower risk of incident dementia. The multivariate-adjusted HRs for the incidence of dementia according to coffee consumption categories (never, occasionally, 1-2 cups/d, and ≥3 cups/d) were 1.00, 0.73 (95% CI, 0.62–0.86), 0.72 (95% CI, 0.61–0.84), and 0.82 (95% CI, 0.65–1.02; p for trend = 0.009), respectively. In addition, this significant inverse association was more remarkable among women, non-smokers, and non-drinkers. Coffee consumption is significantly associated with a lower risk of incident dementia. Show more

Keywords: Coffee, cohort, dementia, elderly, Japan

DOI: 10.3233/JAD-150693

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 491-500, 2016

Authors: Jin, Huafeng | Chen, Tingting | Li, Guoxi | Wang, Conghui | Zhang, Baofeng | Cao, Xinyuan | Sha, Sha | Wan, Qi | Chen, Ling

Article Type: Research Article

Abstract: Background: Simvastatin (SV) has been reported to improve dementia and slow progression of Alzheimer’s disease (AD), however there are conflicting reports. Objective & Methods: Intracerebroventricular injection of aggregated Aβ1-42 in mice (Aβ1-42 -mice) caused spatial cognitive deficits, long-term potentiation (LTP) impairment, and death of hippocampal pyramidal cells. The present study focused on exploring the dose-dependent effects of SV (10–80 mg/kg) on Aβ1-42 -impaired spatial memory and the underlying mechanisms. Results: The treatment of Aβ1-42 -mice with SV for continuous 15 days could attenuate the spatial cognitive deficits and recover the LTP induction in a “U” type …dose-dependent manner. The death of pyramidal cells in Aβ1-42 -mice was significantly reduced by the SV-treatment at 20 mg/kg, but not at a dose of 10 or 40 mg/kg, even was aggravated at a dose of 80 mg/kg. Hippocampal NMDA receptor (NMDAr) NR2B phosphorylation (phospho-NR2B) was elevated in Aβ1-42 -mice, which was further dose-dependently increased by SV-treatment. Replenishment of isoprenoid farnesyl pyrophosphate (FPP) by applying farnesol (FOH) could abolish the SV-increased phospho-NR2B in Aβ1-42 -mice, but had no effect on the Aβ1-42 -enhanced phospho-NR2B. NMDAr antagonist blocked the neurotoxicity of Aβ1-42 and SV (80 mg/kg) in Aβ1-42 -mice, whereas FOH only inhibited SV (80 mg/kg)-neurotoxicity. The SV-treatment in Aβ1-42 -mice corrected the decrease in hippocampal Akt phosphorylation. The PI3K inhibitor abolished the SV (20 mg/kg)-neuroprotection in Aβ1-42 -mice. Conclusion: SV-treatment in Aβ1-42 -mice exerts dose-dependent neuroprotection and neurotoxicity by reducing FPP to enhance the phosphorylation of NR2B and Akt. Show more

Keywords: Amyloid–β 1–42, hippocampus, long-term potentiation, memory, NMDA receptor, simvastatin

DOI: 10.3233/JAD-150782

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 501-516, 2016

Authors: Hatami, Asa | Monjazeb, Sanaz | Glabe, Charles

Article Type: Research Article

Abstract: Recently we reported that several monoclonal antibodies that recognize linear segments of amyloid-β (Aβ) also recognize amyloid fibrils, but not monomers of unrelated sequences, indicating that recognition of a linear sequence segment is not a reliable indicator of sequence specificity. We asked whether any of the commonly used commercially available Aβ antibodies also recognize fibrils of unrelated sequence. Here we report that 4G8, which recognizes residues 18–23 of the Aβ sequence and is widely believed to be sequence-specific, also recognizes fibrils formed from α-synuclein and islet amyloid polypeptide (IAPP). The recognition of amyloid fibrils is aggregation-dependent because 4G8 does not …recognize α-synuclein or IAPP monomer. 4G8 also stains fibrillar α-synuclein aggregates in human multiple system atrophy brain where it colocalizes with anti-α-synuclein monoclonal antibody LB509 immunoreactivity. We also found that LB509 recognizes Aβ fibrils, but not monomer, indicating that generic epitope-reactive antibodies are also produced in response to α-synuclein immunization. Taken together, our results indicate that generic fibril conformational epitope specificity may be a pervasive property among monoclonal antibodies raised against amyloid-forming antigens and that the specificity of their immunoreactivity should be rigorously established and otherwise interpreted with caution. Show more

Keywords: Amyloid, amyloid-beta, conformation, monoclonal antibody, IAPP, synuclein

DOI: 10.3233/JAD-150696

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 517-525, 2016

Authors: Yamashita, Shinji | Kiko, Takehiro | Fujiwara, Hironori | Hashimoto, Michio | Nakagawa, Kiyotaka | Kinoshita, Mikio | Furukawa, Katsutoshi | Arai, Hiroyuki | Miyazawa, Teruo

Article Type: Research Article

Abstract: Aside from accumulation of amyloid-β (Aβ) peptide in the brain, Alzheimer’s disease (AD) has been reported as being associated with peroxidation of major phospholipids (e.g., phosphatidylcholine (PtdCho)) and degradation of antioxidative phospholipids (e.g., ethanolamine plasmalogen (PlsEtn)). In addition to its presence in the brain, Aβ is also found in blood; however, there is still little information about the levels of PtdCho hydroperoxide (PCOOH) and PlsEtn in the blood of patients with AD. In this study, by assuming a possible interaction among Aβ, PCOOH, and PlsEtn in blood circulation, we evaluated the levels of these molecules and correlations in blood samples …that had been obtained from our former AD study for PCOOH measurement (Kiko et al., J Alzheimers Dis 28 , 593-600, 2012). We found that when compared to controls, plasma from patients with AD showed lower concentrations of PlsEtn species, especially PlsEtn bearing the docosahexaenoic acid (DHA) moiety. In addition, lower PlsEtn and higher PCOOH levels were observed in red blood cells (RBCs) of patients with AD. In both AD and control blood samples, RBC PCOOH levels tended to correlate with plasma levels of Aβ40 , and each PlsEtn species showed different correlations with plasma Aβ. These results, together with in vitro data suggesting Aβ aggregation due to a decrease in levels of PlsEtn having DHA, led us to deduce that Aβ is involved in alterations in levels of PCOOH and PlsEtn species observed in the blood of patients with AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, phospholipid hydroperoxide, plasmalogen

DOI: 10.3233/JAD-150640

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 527-537, 2016

Authors: Morenas-Rodríguez, Estrella | Cervera-Carles, Laura | Vilaplana, Eduard | Alcolea, Daniel | Carmona-Iragui, María | Dols-Icardo, Oriol | Ribosa-Nogué, Roser | Muñoz-Llahuna, Laia | Sala, Isabel | Belén Sánchez-Saudinós, M. | Blesa, Rafael | Clarimón, Jordi | Fortea, Juan | Lleó, Alberto

Article Type: Research Article

Abstract: Background: Progranulin is implicated in frontotemporal dementia (FTD), but its role in other neurodegenerative disorders is unknown. Objective: To investigate the levels of progranulin (PGRN) in cerebrospinal fluid (CSF) in different neurodegenerative dementias and their correlation with levels in plasma in cognitively normal subjects. Methods: We measured PGRN in CSF in 229 patients with amnestic mild cognitive impairment, Alzheimer’s disease dementia, sporadic FTD, dementia with Lewy bodies, corticobasal syndrome, or progressive supranuclear palsy. We also measured PGRN in CSF and plasma in 74 cognitively normal individuals. We examined the correlation between PGRN levels in CSF and …diagnosis, cortical thickness, genetic factors and other CSF biomarkers. We also investigated the correlation between plasma and CSF levels of PGRN in cognitively normal individuals. Results: CSF levels did not differ across diagnoses or correlate with cortical thickness. Polymorphism rs5848 in GRN influenced CSF PGRN levels, but APOE ɛ 4 allele did not. Amyloid-β 42 , t-tau, p-tau, and YKL-40 levels correlated weakly with PGRN in CSF. We found a weak correlation (r  = 0.362) between plasma and CSF PGRN levels in cognitively normal individuals. Conclusions: Our findings do not support a diagnostic value of CSF PGRN in neurodegenerative diseases. Our data confirm that levels of PGRN in plasma do not reflect accurately levels in CSF in cognitively normal controls. These data should be considered in clinical trials aiming to increase PGRN. Show more

Keywords: Alzheimer’s disease, amyloid-β, biomarker, cerebrospinal fluid, dementia, plasma, progranulin, tau

DOI: 10.3233/JAD-150746

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 539-546, 2016

Authors: Oulhaj, Abderrahim | Jernerén, Fredrik | Refsum, Helga | Smith, A. David | de Jager, Celeste A.

Article Type: Research Article

Abstract: A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores …for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD. Show more

Keywords: Alzheimer’s disease, B vitamins, clinical dementia rating scale, cognition, omega–3 fatty acids

DOI: 10.3233/JAD-150777

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 547-557, 2016

Authors: Ibarria, Marta | Alegret, Montserrat | Valero, Sergi | Morera, Amèrica | Guitart, Marina | Cañabate, Pilar | Moreno, Mariola | Lara, Susana | Diego, Susana | Hernández, Joan | Tantinyá, Natàlia | Vera, Maribel | Hernández, Isabel | Becker, James T. | Ruíz, Agustín | Boada, Mercè | Tárraga, Lluís

Article Type: Research Article

Abstract: Background: The existing pharmacological treatments for Alzheimer’s disease (AD) can only slow the progression of symptoms or delay admission to long-term care facilities. The beneficial effects of non-drug treatments are poorly studied. Objective: To describe the effects of an Integrated Psychostimulation Program (IPP) in patients with mild-moderate AD treated with acetylcholinesterase inhibitors; and to identify factors related to greater benefit of the IPP. Methods: 206 patients (mean age = 75.9 years; MMSE = 19.6) were evaluated before starting the IPP and 3, 6, 9, and 12 months later. Measures included: Mini-Mental State Examination (MMSE), Cognitive Subscale of Alzheimer’s Disease Assessment …Scale (ADAS-Cog), Rapid Disability Rating Scale (RDRS-2), and Neuropsychiatric Inventory Questionnaire (NPI-Q). Results: Patients remained cognitively stable (MMSE/ADAS-Cog) for more than 6 months and significantly worsened at 9-month and 12-month follow-ups, without clinically significant functional changes (RDRS-2) or psychiatric symptoms(NPI-Q). The mean annual change on MMSE and ADAS-Cog were 2.06 and 3.56 points, respectively, lower than the annual decline demonstrated previously in similar patients (2.4 and 4.5, respectively). 42.7% of patients maintained or improved global cognitive scores between baseline and 12-month follow-up. The patients who maintained cognitive functions were older than those who did not (77.5 versus 74.7 years). Conclusions: The IPP may be an effective treatment to maintain cognition, functionality, and psychiatric symptoms in AD patients pharmacologically treated, and older age seems to increase beneficial effects of IPP. Show more

Keywords: Alzheimer’s disease, cognition, cognitive stimulation, dementia, functionality, Integral Psychostimulation Program, non-pharmacological therapy

DOI: 10.3233/JAD-150455

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 559-566, 2016

Authors: Vijayaraghavan, Swetha | Darreh-Shori, Taher | Rongve, Arvid | Berge, Guro | Sando, Sigrid B. | White, Linda R. | Auestad, Bjørn H. | Witoelar, Aree | Andreassen, Ole A. | Ulstein, Ingun D. | Aarsland, Dag

Article Type: Research Article

Abstract: Background: A common polymorphism of the butyrylcholinesterase gene, the K-variant (BCHE-K) is associated with reduced butyrylcholinesterase (BuChE) activity. Insufficient studies exist regarding the frequency and role of BCHE-K in dementias. Objective: To determine the association of BCHE-K and APOE ɛ 4 with diagnosis and rate of cognitive decline in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) patients. Methods: Genomic DNA from 368 subjects (108 AD, 174 DLB, and 86 controls) from two routine clinical cohort studies in Norway; DemVest and TrønderBrain, were genotyped for BCHE-K and APOE ɛ …4. The mild dementia DemVest subjects received annual Mini-Mental State Examination assessments for five years. Results: BCHE-K frequency was lower in DLB (33.9% ; p  <  0.01) than in control subjects (51.2%), and was numerically lower in AD as well (38.9% ; p  = 0.11). More rapid cognitive decline was associated with the APOE ɛ 4 genotype, but not with the BCHE-K genotype. In an exploratory analysis of patients who completed all five follow-up visits, there was greater cognitive decline in BCHE-K carriers in the presence of the APOE ɛ 4 allele than in the absence of these polymorphisms. Conclusion: BCHE-K is associated with a reduced risk for AD and DLB whereas APOE ɛ 4 is associated with more rapid cognitive decline. The greater cognitive decline in individuals with both APOE ɛ 4 and BCHE-K alleles require prospective confirmation in well-controlled trials. Show more

Keywords: Apolipoprotein E genotype, butyrylcholinesterase-K, cognition, dementia, Mini-Mental State Examination

DOI: 10.3233/JAD-150750

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 567-576, 2016

Authors: Mudar, Raksha A. | Chiang, Hsueh-Sheng | Eroh, Justin | Nguyen, Lydia T. | Maguire, Mandy J. | Spence, Jeffrey S. | Kung, Fanting | Kraut, Michael A. | Hart Jr., John

Article Type: Research Article

Abstract: We examined the effects of amnestic mild cognitive impairment (aMCI) on behavioral (response times and error rates) and scalp-recorded event-related potential (ERP) measures of response execution and inhibition, using Go/NoGo tasks involving basic and superordinate semantic categorization. Twenty-five aMCI (16 F; 68.5±8 years) and 25 age- and gender-matched normal control subjects (16 F; 65.4±7.1 years) completed two visual Go/NoGo tasks. In the single car task, responses were made based on single exemplars of a car (Go) and a dog (NoGo) (basic). In the object animal task, responses were based on multiple exemplars of objects (Go) and animals (NoGo) (superordinate). The …aMCI subjects had higher commission errors on the NoGo trials compared to the control subjects, whereas both groups had comparable omission errors and reaction times during the Go trials. The aMCI subjects had significantly prolonged N2 ERP latency during Go and NoGo trials across tasks compared to the controls. Both groups showed similar categorization effects and response type effects in N2/P3 ERP latencies and P3 amplitude. Our findings indicate that altered early neural processing indexed by N2 latency distinguishes subjects with aMCI from controls during the Go/NoGo task. Prolonged Go-N2 latency in aMCI appears to precede behavioral changes in response execution, whereas prolonged NoGo-N2 latency underlies behavioral deterioration in response inhibition. Show more

Keywords: Categorization, cognition, electroencephalography, event-related potentials, Go/NoGo, mild cognitive impairment, semantics

DOI: 10.3233/JAD-150586

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 577-590, 2016

Authors: Makovac, Elena | Serra, Laura | Spanò, Barbara | Giulietti, Giovanni | Torso, Mario | Cercignani, Mara | Caltagirone, Carlo | Bozzali, Marco

Article Type: Research Article

Abstract: Behavioral disorders and psychological symptoms (BPSD) in Alzheimer’s disease (AD) are known to correlate with grey matter (GM) atrophy and, as shown recently, also with white matter (WM) damage. WM damage and its relationship with GM atrophy are reported in AD, reinforcing the interpretation of the AD pathology in light of a disconnection syndrome. It remains uncertain whether this disconnection might account also for different BPSD observable in AD. Here, we tested the hypothesis of different patterns of association between WM damage of the corpus callosum (CC) and GM atrophy in AD patients exhibiting one of the following BPSD clusters: …Mood (i.e., anxiety and depression; ADmood ), Frontal (i.e., dishinibition and elation; ADfrontal ), and Psychotic (delusions and hallucinations; ADpsychotic ) related symptoms, as well as AD patients without BPSD. Overall, this study brings to light the strict relationship between WM alterations in different parts of the CC and GM atrophy in AD patients exhibiting BPSD, supporting the hypothesis that such symptoms are likely to be caused by characteristic patterns of neurodegeneration of WM and GM, rather than being a reactive response to accumulation of cognitive disabilities, and should therefore be regarded as potential markers of diagnostic and prognostic value in AD. Show more

Keywords: Alzheimer’s disease, behavioral, grey matter, magnetic resonance imaging, white matter

DOI: 10.3233/JAD-150612

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 591-604, 2016

Authors: Koch, Giacomo | Di Lorenzo, Francesco | del Olmo, Miguel Fernandez | Bonní, Sonia | Ponzo, Viviana | Caltagirone, Carlo | Bozzali, Marco | Martorana, Alessandro

Article Type: Research Article

Abstract: Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer’s disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) …and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline. Show more

Keywords: Alzheimer’s disease, amyloid-beta, cortical plasticity, long-term depression, long-term potentiation, tau, transcranial magnetic stimulation

DOI: 10.3233/JAD-150813

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 605-616, 2016

Article Type: Other

DOI: 10.3233/JAD-151064

Citation: Journal of Alzheimer's Disease, vol. 50, no. 2, pp. 617-621, 2016