Journal of Alzheimer's Disease - Volume 61, issue 4

Authors: Nakaizumi, Kyoko | Ouchi, Yasuomi | Terada, Tatsuhiro | Yoshikawa, Etsuji | Kakimoto, Akihiro | Isobe, Takashi | Bunai, Tomoyasu | Yokokura, Masamichi | Suzuki, Katsuaki | Magata, Yasuhiro

Article Type: Research Article

Abstract: Background: The α7 subtype of the nicotinic acetylcholine receptor (nAChR) is considered important in higher cognitive functions, and cholinergic loss underpins the pathophysiology of Alzheimer’s disease (AD). However, the relationships between α7 nAChR function and clinical functions or amyloid-β (Aβ) deposition remain to be explored in the living AD brain. Objective: We aimed to elucidate the relationship between α7 nAChR availability in the specific cholinergic region and cognitive decline in the Aβ-confirmed AD brain. Methods: Twenty AD patients and ten age-matched healthy subjects were examined. The α7-nAChR availability and Aβ deposition were evaluated using positron emission …tomography with an α7 nAChR radiotracer 11 C-(R )-MeQAA and 11 C-Pittsburg compound B (11 C-PiB), respectively. Semi-quantified values of tracer binding were estimated with a simplified reference tissue method for BPND of 11 C-(R )-MeQAA and a tissue ratio method for SUVR of 11 C-PiB. These parameters and clinical scores were compared voxel-wise using a statistical parametric mapping method. Results: The levels of 11 C-(R )-MeQAA BPND in the temporal and prefrontal cholinergic projection regions were significantly lower in AD, and negative correlations were found between 11 C-PiB SUVR and 11 C-(R )-MeQAA BPND in the region of the nucleus basalis magnocellularis and medial prefrontal cortex. Levels of 11 C-(R )-MeQAA BPND were significantly correlated with memory and frontal function scores in AD. Conclusion: The association between Aβ burden and α7-nAChR reduction in the basal forebrain cholinergic system was highlighted in relation to cognitive decline in AD. This suggests that Aβ-linked α7-nAChR reduction is clinico-pathophyisologically important for considering a good therapeutic target in AD. Show more

Keywords: α7 nicotinic acetylcholine receptor, Alzheimer’s disease, frontal assessment battery, nucleus basalis magnocellularis, positron emission tomography

DOI: 10.3233/JAD-170591

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1355-1365, 2018

Authors: Hallikainen, Ilona | Hongisto, Kristiina | Välimäki, Tarja | Hänninen, Tuomo | Martikainen, Janne | Koivisto, Anne M.

Article Type: Research Article

Abstract: Background: An improved understanding of the role of neuropsychiatric symptoms (NPS) in the course of Alzheimer’s disease (AD) has recently emerged. NPS lead to hospitalization and caregiver stress, but are more variable during the course of the disease than other symptoms. Knowledge about the role of specific NPS in disease progression and prognosis is especially limited. Objectives: To examine the relationship between specific NPS and AD severity during a 5-year follow-up period, and to determine which baseline NPS predict AD progression. Methods: 236 persons with very mild (CDR 0.5) or mild (CDR 1) AD at baseline …and their caregivers were followed up for five years as part of the ALSOVA study. The Neuropsychiatric Inventory was used to assess NPS, and AD severity progression was measured with the Clinical Dementia Rating Sum of Boxes. Data was analyzed with Generalized Estimated Equations and Linear Mixed Models. Results: The baseline NPS that best predicted AD progression were delusions, agitation, and aberrant motor behavior, while AD severity during follow-up was associated with hallucinations, delusions, agitation, apathy, aberrant motor behavior, and sleep and appetite disturbances. Conclusions: Persons with mild AD presenting delusions, agitation, and aberrant motor behavior at the time of diagnosis could have a more rapidly progressing disease, and some NPS are associated with AD severity. These results highlight the importance of evaluating NPS at the time of AD diagnosis, and the need to offer additional support to persons presenting delusions, agitation and aberrant motor behavior, and their caregivers. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, dementia, neuropsychiatry

DOI: 10.3233/JAD-170697

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1367-1376, 2018

Authors: Kim, Jaeho | Park, Seongbeom | Yoo, Heejin | Jang, Hyemin | Kim, Yeshin | Kim, Ko Woon | Jang, Young Kyoung | Lee, Jin San | Kim, Sung Tae | Kim, Seonwoo | Lee, Jong Min | Ki, Chang-Seok | Na, Duk L. | Seo, Sang Won | Kim, Hee Jin

Article Type: Research Article

Abstract: We evaluated how the impact of apolipoprotein E4 (APOE4 ) differs according to age in Alzheimer’s disease (AD) patients. We recruited 846 AD patients and 815 cognitively normal controls and categorized into three groups with respect to their age (<65, 65–74, and ≥75 years). We evaluated the risk of AD in APOE4 carriers and compared cortical thickness and cognitive function according to APOE4 status in each age group. At the point of this study, in young (<65 years) AD, APOE4 noncarriers had the most severe frontal and perisylvian atrophy, while in old (≥75 years) AD, APOE4 …carriers had the most severe medial temporal atrophy. In AD under 75 years, APOE4 noncarriers and heterozygotes showed worse performance in language, visuospatial, and frontal function compared to homozygotes, while, in old (≥75 years) AD, APOE4 homozygotes showed worse performance in memory compared to noncarriers. As the detrimental effects of APOE4 seen in older AD patients were not found in younger AD patients, we suggest that some unrevealed factors are associated with cortical atrophy and non-amnestic cognitive dysfunction in young AD with APOE4 noncarriers. Show more

Keywords: Apolipoprotein E4 (APOE4), Alzheimer’s disease, cognitive dysfunction, magnetic resonance imaging

DOI: 10.3233/JAD-170556

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1377-1385, 2018

Authors: Cosentino, Stephanie | Devanand, Davangere | Gurland, Barry

Article Type: Research Article

Abstract: Subjective impairment in memory is a frequently defining feature of subjective cognitive decline (SCD), a state hypothesized to precede objectively apparent cognitive symptoms of Alzheimer’s disease (AD) and to hold promise as a non-invasive, inexpensive, preclinical indicator of AD. However, a full model of the factors that contribute to subjective memory (SM), and therefore to SCD, has yet to be articulated. While SM impairment is widely known to be associated with negative affect, the extent to which SM functioning may also reflect other factors, particularly subjective beliefs or perceptions about one’s health, is not known. To examine the extent to …which SM is associated with subjective perceptions of health more broadly, the current study investigated the link between SM and subjective physical functioning (independent of depressive affect, and objective cognitive and physical function) in an ethnically diverse sample of 471 older adults enrolled in the population-based Northern Manhattan Aging Project. 199 (42%) participants endorsed no difficulty on a 5-point SM index while 272 (58%) endorsed some degree of difficulty. As hypothesized, SM correlated with both depression and subjective physical function, but not with age, education, global cognition, or objective physical function. When objective and subjective physical function were entered in two separate, adjusted linear regressions predicting SM, only subjective physical function and depressive affect independently predicted SM. Subjective perceptions of memory appear to reflect individuals’ broader health perceptions in part. Articulating the various correlates of SM will improve identification of SCD specific to preclinical AD. Show more

Keywords: Memory complaints, preclinical Alzheimer’s disease, subjective cognition, subjective cognitive decline, subjective memory

DOI: 10.3233/JAD-170495

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1387-1398, 2018

Authors: Gurel, Busra | Cansev, Mehmet | Sevinc, Cansu | Kelestemur, Seda | Ocalan, Busra | Cakir, Aysen | Aydin, Sami | Kahveci, Nevzat | Ozansoy, Mehmet | Taskapilioglu, Ozlem | Ulus, Ismail Hakki | Başar, Merve Karayel | Sahin, Betul | Tuzuner, Mete Bora | Baykal, Ahmet Tarik

Article Type: Research Article

Abstract: In recent years, an increasing number of research papers revealed that the compositional and volumetric alterations in the extracellular matrix are the consequences of aging and may be related to Alzheimer’s disease (AD). In this study, we aimed to demonstrate the alterations in hippocampal extracellular fluid proteins in vivo using the 5XFAD mouse model. Samples were obtained from hippocampi of 5XFAD mice (n  = 6) and their non-transgenic littermates by intracerebral push-pull perfusion technique at 3 months of age, representing the pre-pathological stage of the AD. Proteins in the hippocampal perfusates were analyzed by Ultra Performance Liquid Chromatography-Electrospray Ionization Quadrupole …Time-of-Flight Mass Spectrometry (UPLC-ESI-qTOF-MS/MS). 178 proteins were identified and 19 proteins of them were found to be statistically significantly altered (p ≤0.05, fold change ≥40%, unique peptide count ≥3) in the hippocampal CA1 extracellular fluid of the 5XFAD mouse model. Ingenuity pathway analysis of the protein expression results identified IL6 as an upstream regulator. The upregulation of IL6 was validated by immunohistochemical staining of the hippocampus and cortex of the 5XFAD mice prior to Aβ plaque formation. Furthermore, the iron level in the hippocampus was measured by inductively coupled plasma-mass spectrometry as IL6 is mentioned in several studies to take part in iron homeostasis and inflammation and found to be increased in 5XFAD mice hippocampus. Alterations in extracellular matrix proteins in addition to increasing amount of hippocampal IL6 and iron in the early stages of AD may reveal inflammation-mediated iron dyshomeostasis in the early stages of neurodegeneration. Show more

Keywords: Alzheimer’s disease, extracellular matrix, IL6, iron, neuroinflammation, proteomics

DOI: 10.3233/JAD-170329

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1399-1410, 2018

Authors: Yu, Linjie | Liu, Yi | Jin, Yuexinzi | Cao, Xiang | Chen, Jian | Jin, Jiali | Gu, Yue | Bao, Xinyu | Ren, Zhuoying | Xu, Yun | Zhu, Xiaolei

Article Type: Research Article

Abstract: Amyloid-β (Aβ) induces a burst of oxidative stress and plays a critical role in the pathogenesis of Alzheimer’s disease (AD). Our previous results have shown that histone deacetylase 3 (HDAC3) inhibition ameliorates spatial memory deficits and decreases the Aβ burden in the brains of 9-month-old APPswe/PS1dE9 (APP/PS1) mice. In this study, we investigated the role of HDAC3 inhibition in oxidative stress in vivo and in vitro models of AD. HDAC3 was detected mainly in the neurons, and HDAC3 inhibition significantly decreased reactive oxygen species generation and improved primary cortical neuron viability. In addition, HDAC3 inhibition attenuated spatial memory …dysfunction in 6-month-old APP/PS1 mice, and decreased the apoptotic rate in the hippocampi as demonstrated by TUNEL staining. HDAC3 inhibition also reduced markers of lipid peroxidation, protein oxidation, and DNA/RNA oxidation in the hippocampi of APP/PS1 mice. Moreover, HDAC3 inhibition inactivated the c-Abl/MST1/YAP signaling pathway in the hippocampi of APP/PS1 mice. In conclusion, our data show that HDAC3 inhibition can attenuate spatial memory deficits and inhibit oxidative stress in APP/PS1 mice; these results indicate a potential strategy for AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, Hippo signaling pathway, histone deacetylase 3, oxidative stress

DOI: 10.3233/JAD-170844

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1411-1424, 2018

Authors: Ahlemeyer, Barbara | Halupczok, Sascha | Rodenberg-Frank, Elke | Valerius, Klaus-Peter | Baumgart-Vogt, Eveline

Article Type: Research Article

Abstract: Amyloid-β peptide (Aβ), paired helical filament-tau (PHF-tau), and α-synuclein are in the focus of neuroscience research because they aggregate in brains of patients with Alzheimer’s and Parkinson’s diseases. For this purpose, transgenic mouse models were used containing the human genes for AβPP/presenilin/tau or α-synuclein with the most frequent mutations. This is not ideal because most patients develop sporadic forms of the diseases with no causative single gene defect and furthermore the aggregation of human proteins in man is not necessarily the same in rodents. We hypothesized that for such cases the aged mouse could be an alternative model and analyzed …the distribution of endogenous Aβ, PHF-tau, and α-synuclein in mouse brains at different ages. Whereas Aβ was below detectable levels at birth, it was present at high levels in the 15-month-old mouse. Aβ was found in the cytosol and lysosomes of neurons of the temporal cortex, cingulate area, pons, and cerebellum as well as extracellularly in the periventricular zone. Contrary to Aβ, mouse brain was devoid of PHF-tau-positive neurofibrillary tangles. α-Synuclein was detectable in the newborn mouse with highest levels in the marginal zone of the lateral cortex and average levels in the hippocampus, pons, and cerebellum. Brain-area specific differences in the α-synuclein level persisted up to 15 months of age, but increased 3-fold in all areas over time. α-Synuclein resided in the neuropil, but not in intracellular aggregates even in the aged mouse. We suggest the aged mouse as a model to study Aβ plaque formation. Show more

Keywords: Aged mouse, amyloid-β peptides, α-synuclein, extracellular aggregates, PHF-tau, brain regions

DOI: 10.3233/JAD-170923

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1425-1450, 2018

Authors: Libard, Sylwia | Laurell, Katarina | Cesarini, Kristina Giuliana | Alafuzoff, Irina

Article Type: Research Article

Abstract: We had an opportunity to assess the change observed in the brain regarding Alzheimer’s disease (AD)-related alterations, cell count, and inflammation that took place during a period of 21 months in a subject with a definite diagnosis of AD and idiopathic Normal Pressure Hydrocephalus (iNPH). Four neuronal markers, i.e., synaptophysin, microtubule associated protein 2, non-phosphorylated neurofilament H (SMI32), and embryonic lethal abnormal visual system proteins 3/4 HuC/HuD (HuC/HuD); three microglial markers CD68, Human Leucocytic Antigen DR, ionized calcium-binding adaptor molecule 1, glial fibrillary acidic protein (GFAP); and AD-related markers, hyperphosphorylated τ (HPτ ) and amyloid-β (Aβ, Aβ40 , Aβ42 …) were assessed. Morphometrically assessed immunoreactivity of all neuronal and all microglial markers and Aβ42 decreased parallel with an increase in the HPτ in the frontal cortex. The expression of GFAP was stable with time. The first sample was obtained during the therapeutic shunting procedure for iNPH, and the second sample was obtained postmortem. Negligible reactive changes were observed surrounding the shunt channel. In conclusion, in the late stage of AD with time, a neuronal loss, increase in the HPτ , and decrease in Aβ42 and microglia was observed, whereas the expression of GFAP was rather stable. The observations described here suggest that when a brain biopsy has been obtained from an adult subject with iNPH, the assessment of postmortem brain is of major significance. Show more

Keywords: Amyloid-β, astrocytes, hyperphosphorylated tau, idiopathic normal pressure hydrocephalus, immunohistochemistry, microglia, neurons

DOI: 10.3233/JAD-170446

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1451-1462, 2018

Authors: González-Ramírez, Mariela | Gavilán, Javiera | Silva-Grecchi, Tiare | Cajas-Madriaga, Daniel | Triviño, Sergio | Becerra, José | Saez-Orellana, Francisco | Pérez, Claudia | Fuentealba, Jorge

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is characterized by amyloid plaques that form due to an increase in amyloid-β peptide (Aβ) aggregation. One strategy in the search of new treatments for AD focuses on compounds that decrease Aβ accumulation. Compounds containing a benzofuran ring have been described to play an important role in decreasing Aβ-induced toxicity; however, only synthetic benzofurans have been tested thus far. The aim of the present study was to examine the in vitro neuroprotective properties of fomannoxin (Fx), a natural benzofuran isolated from cultures of the Andean-Patagonian fungi Aleurodiscus vitellinus , and evaluate its effect on Aβ peptide. …We tested the effect of Fx at a wide concentration range (10–11 –10–4 M) in PC-12 cells, and found the compound did not alter cellular viability. Fx also showed a concentration-dependent effect on the Aβ-induced toxicity in PC12 cells, showing viability above 100% at 10–6 M. We then measured the effect of Fx (10–7 –10–5 M) on the frequency of cytosolic Ca2+ transients in rat hippocampal neurons at both acute and chronic (24 h) times. Acute incubation with Fx increased the frequency of cytosolic Ca2+ transients to values around 200%, whereas chronic incubation with Fx increased the frequency of Ca2+ transients. Finally, the Aβ-induced decrease in intracellular Ca2+ transients was prevented when Fx (10–6 M) was co-incubated with Aβ (5×10–6 M). The results suggest a potent neuroprotective effect of this naturally occurring benzofuran against Aβ peptide toxicity that could be mediated by an interference with it binding to plasma membrane, and lead Fx as new chemical entity to develop pharmacological tools against Aβ peptide neurotoxicity. Show more

Keywords: Alzheimer’s disease, Aβ peptide inhibitor, benzofuran, fomannoxin

DOI: 10.3233/JAD-170958

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1463-1475, 2018

Authors: Saraceno, Claudia | Catania, Marcella | Paterlini, Anna | Fostinelli, Silvia | Ciani, Miriam | Zanardini, Roberta | Binetti, Giuliano | Di Fede, Giuseppe | Caroppo, Paola | Benussi, Luisa | Ghidoni, Roberta | Bolognin, Silvia

Article Type: Research Article

Abstract: The term frontotemporal lobar degeneration (FTLD) defines a group of heterogeneous conditions histologically characterized by neuronal degeneration, inclusions of various proteins, and synaptic loss. However, the molecular mechanisms contributing to these alterations are still unknown. As the Rho-GTPase family member Cell division cycle 42 (Cdc42) plays a key role in the regulation of actin cytoskeleton dynamics and spine formation, we investigated whether Cdc42 protein levels were altered in the disease. Cdc42 was increased in the frontal cortex of FTLD patients compared to age-matched controls, but also in Alzheimer’s disease (AD) patients included in the data-set. On the other hand, the …pool of circulating Cdc42 in the plasma was altered in FTLD but not in AD patients. Interestingly, the stratification of the FTLD patients according to the different clinical variants showed a specific decrease of Cdc42 expression in the behavioral subgroup. This data support a role of Cdc42 in FTLD and specifically in the behavioral variant. Show more

Keywords: Alzheimer’s disease, biomarkers, Cdc42, frontotemporal dementia, plasma, Rho-GTPases

DOI: 10.3233/JAD-170722

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1477-1483, 2018