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

Authors: Kaindlstorfer, Christine | Jellinger, Kurt A. | Eschlböck, Sabine | Stefanova, Nadia | Weiss, Günter | Wenning, Gregor K.

Article Type: Review Article

Abstract: Iron is essential for cellular development and maintenance of multiple physiological processes in the central nervous system. The disturbance of its homeostasis leads to abnormal iron deposition in the brain and causes neurotoxicity via generation of free radicals and oxidative stress. Iron toxicity has been established in the pathogenesis of Parkinson’s disease; however, its contribution to multiple system atrophy (MSA) remains elusive. MSA is characterized by cytoplasmic inclusions of misfolded α-synuclein (α-SYN) in oligodendrocytes referred to as glial cytoplasmic inclusions (GCIs). Remarkably, the oligodendrocytes possess high amounts of iron, which together with GCI pathology make a contribution toward MSA pathogenesis …likely. Consistent with this observation, the GCI density is associated with neurodegeneration in central autonomic networks as well as olivopontocerebellar and striatonigral pathways. Iron converts native α-SYN into a β-sheet conformation and promotes its aggregation either directly or via increasing levels of oxidative stress. Interestingly, α-SYN possesses ferrireductase activity and α-SYN expression underlies iron mediated translational control via RNA stem loop structures. Despite a correlation between progressive putaminal atrophy and iron accumulation as well as clinical decline, it remains unclear whether pathologic iron accumulation in MSA is a secondary event in the cascade of neuronal degeneration rather than a primary cause. This review summarizes the current knowledge of iron in MSA and gives evidence for perturbed iron homeostasis as a potential pathogenic factor in MSA-associated neurodegeneration. Show more

Keywords: Iron, multiple system atrophy, α-SYN, neurodegeneration, Parkinson’s disease

DOI: 10.3233/JAD-170601

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1253-1273, 2018

Authors: Gómez-Tortosa, Estrella | Ruggiero, María | Sainz, Ma José | Villarejo-Galende, Alberto | Prieto-Jurczynska, Cristina | Venegas Pérez, Begoña | Ordás, Carlos | Agüero, Pablo | Guerrero-López, Rosa | Pérez-Pérez, Julián

Article Type: Short Communication

Abstract: The SORL1 gene encodes a protein involved in the amyloidogenic process, and its variants have been associated with Alzheimer’s disease (AD) physiopathology. We screened for SORL1 variants in 124 familial (44 early- and 80 late-onset) dementia of Alzheimer type (DAT) cases. Nine potentially pathogenic changes (three not previously reported and six rare variants) were found in nine probands (7%). After screening the control population and siblings (presence in at least 1/200 controls and/or absence of segregation pattern), a causal relationship with the disease was considered unlikely in six variants and uncertain in one. The change Trp848Ter and a …splice-site variant remained likely correlated with the disease. SORL1 mutations are present in 7% of our familial DAT cohort, though in most cases cannot be considered the direct cause of the disease. Show more

Keywords: Alzheimer’s disease, familial, neurogenetics, SORL1 gene, SORLA protein

DOI: 10.3233/JAD-170590

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1275-1281, 2018

Authors: Che, Xiang-Qian | Zhao, Qian-Hua | Huang, Yue | Li, Xia | Ren, Ru-Jing | Chen, Sheng-Di | Guo, Qi-Hao | Wang, Gang

Article Type: Short Communication

Abstract: As an important multifunctional protein involved in regulation of mitochondrial metabolism, CHCHD2 was identified as a causative gene for Parkinson’s disease (PD), yet the relationship between CHCHD2 and neurodegenerative dementia is not well understood. We directly sequenced the entire coding region of CHCHD2 gene in 150 AD patients, 84 FTD patients, and 417 controls. Four rare putative pathogenic variants of CHCHD2 , including rs142444896 (c.5C>T, p.P2L), rs752705344 (c.15C>G, p.S5R), rs145190179 (c.94G>A, p.A32T), and rs182992574 (c.255T>A, p.S85R) were identified from a cohort composed of 150 AD and 84 FTD patients. These results suggest the CHCHD2 gene may …an important role in other neurodegenerative disorders from our dementia study in China. Show more

Keywords: Alzheimer’s disease, CHCHD2, dementia, frontotemporal dementia

DOI: 10.3233/JAD-170692

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1283-1288, 2018

Authors: Serpente, Maria | Fenoglio, Chiara | Cioffi, Sara Maria Giulia | Oldoni, Emanuela | Arcaro, Marina | Arighi, Andrea | Fumagalli, Giorgio Giulio | Ghezzi, Laura | Scarpini, Elio | Galimberti, Daniela

Article Type: Short Communication

Abstract: Herein, we performed a gene expression profiling in a cohort of 10 mild cognitive impairment (MCI), subdivided, according to the analysis of cerebrospinal fluid biomarkers, in prodromal Alzheimer’s disease (AD) and non-AD MCI, as compared with 27 AD patients and 24 controls, in order to detect early gene expression alterations. We observed a significant upregulation of insulin (INS ) and INS Receptor (INSR) expression levels in AD both prodromal and fully symptomatic, as compared with controls, but not in MCI subjects. Our results suggest an early dysregulation of INS and INSR in AD pathogenesis and pave the …way to a possible utility of these transcripts as peripheral biomarkers. Show more

Keywords: Gene expression, insulin, insulin receptor, peripheral biomarkers, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-170861

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1289-1294, 2018

Authors: Clemens, Vera | Regen, Francesca | Le Bret, Nathalie | Heuser, Isabella | Hellmann-Regen, Julian

Article Type: Short Communication

Abstract: Apolipoprotein E (ApoE) represents a pivotal target in Alzheimer’s disease (AD) and is modulated through retinoic acid (RA), an endogenous neuroprotective and anti-inflammatory compound. A major source of ApoE are microglia, which are pathologically activated in AD. Activated microglia are known to block RA signaling. This suggests a vicious cycle between inflammation, RA signaling, and ApoE homeostasis in AD pathogenesis. To test this hypothesis, we investigated effects of RA and proinflammatory activation on ApoE synthesis in primary human macrophage-derived microglial-like cells. Our results indicate that proinflammatory activation attenuates ApoE synthesis, an effect blocked by RA.

Keywords: Alzheimer’s disease, Apolipoprotein E, macrophages, retinoic acid, vitamin A

DOI: 10.3233/JAD-170823

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1295-1300, 2018

Authors: Rizzuto, Debora | Feldman, Adina L. | Karlsson, Ida K. | Dahl Aslan, Anna K. | Gatz, Margaret | Pedersen, Nancy L.

Article Type: Research Article

Abstract: Background: Population-based health registers are potential assets in epidemiological research; however, the quality of case ascertainment is crucial. Objective: To compare the case ascertainment of dementia, from the National Patient Register (NPR) and the Cause of Death Register (CDR) with dementia diagnoses from six Swedish population based studies. Methods: Sensitivity, specificity, and positive predictive value (PPV) of dementia identification in NPR and CDR were estimated by individual record linkage with six Swedish population based studies (n  = 19,035). Time to detection in NPR was estimated using data on dementia incidence from longitudinal studies with more than two …decades of follow-up. Results: Barely half of the dementia cases were ever detected by NPR or CDR. Using data from longitudinal studies we estimated that a record with a dementia diagnosis appears in the NPR on average 5.5 years after first diagnosis. Although the ability of the registers to detect dementia cases was moderate, the ability to detect non-dementia cases was almost perfect (99%). When registers indicate that there is a dementia diagnosis, there are very few instances in which the clinicians determined the person was not demented. Indeed, PPVs were close to 90%. However, misclassification between dementia subtype diagnoses is quite common, especially in NPR. Conclusions: Although the overall sensitivity is low, the specificity and the positive predictive value are very high. This suggests that hospital and death registers can be used to identify dementia cases in the community, but at the cost of missing a large proportion of the cases. Show more

Keywords: Alzheimer’s disease, dementia, population-based registers, validation study, vascular dementia

DOI: 10.3233/JAD-170572

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1301-1310, 2018

Authors: Lu, Jing | Shu, Runzhe | Zhu, Yan

Article Type: Research Article

Abstract: SFPQ (Splicing factor proline- and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair. SFPQ was found dysregulated in a few tauopathies such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In addition, knock-down of SFPQ induced FTD-like behavior in mouse. To confirm the role of SFPQ in AD and FTD, we analyzed the brain sections from the AD and FTD brain samples with SFPQ upregulation and dislocation. Specifically, we observed SFPQ dislocated to the cytoplasm and nuclear envelopes, and DNA structures and organizations were associated with these dislocation phenotypes in AD …and FTD brains. Consistently, we also found decreased DAPI intensities and smaller chromocenters associated with SFPQ dislocation in nerural-2a (N2a) cells. As the upregulation and hyperphosphorylation of tau protein is a hallmark of AD and FTD, our study sought to investigate potential interactions between tau and SFPQ by co-transfection and co-immunoprecipitation assays in N2a cells. SFPQ dislocation was found enhanced with tau co-transfection and tau co-transfection further resulted in extended DNA disorganization in N2a cells. Overall, our results indicate that dysregulation and dislocation of SFPQ and subsequent DNA disorganization might be a novel pathway in the progression of AD and FTD. Show more

Keywords: Alzheimer’s disease, DNA organization, dislocation, splicing factor proline- and glutamine-rich, tau

DOI: 10.3233/JAD-170659

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1311-1321, 2018

Authors: Yang, Che-Chuan | Chiu, Ming-Jang | Chen, Ta-Fu | Chang, Hui-Ling | Liu, Bing-Hsien | Yang, Shieh-Yueh

Article Type: Research Article

Abstract: The feasibility of assaying plasma phosphorylated tau protein (threonine 181), denoted p-tau181, using immunomagnetic reduction (IMR) is explored. The reagent for assaying p-tau181 with IMR was synthesized, and its analytic performances were characterized. Seventy-three subjects were recruited. Each participant was examined with neuropsychological tests, magnetic resonance imaging, and IMR assay for plasma p-tau181. Using commercially available IMR kits, the plasma total tau protein (T-tau) of each subject was assayed. The dynamic range for assaying p-tau181 using IMR was 1.96×10-2 pg/ml to 104 pg/ml. There was no significant interference from total tau protein in the assay of p-tau181. The …measured concentrations of plasma p-tau181 were 2.46±1.09 pg/ml for healthy controls, 4.41±1.85 pg/ml for MCI due to AD, and 6.14±1.59 pg/ml for very mild AD. Meanwhile, the measured concentrations of plasma T-tau were 18.85±10.16 pg/ml for healthy controls, 32.98±10.18 pg/ml for MCI due to AD, and 37.54±12.29 pg/ml for very mild AD. A significant difference in plasma p-tau181 was observed between healthy controls and MCI due to AD (p  < 0.001) and between MCI due to AD and very mild AD (p  < 0.001). However, for the plasma T-tau concentration, a significant difference existed only between healthy controls and MCI due to AD (p  < 0.001). This implies that the plasma p-tau181 level is correlated more to AD severity than plasma T-tau is. Additionally, p-tau181 was observed as approximately 14% of T-tau in human plasma. Show more

Keywords: Alzheimer’s disease, human plasma, immunomagnetic reduction, phosphorylated tau protein, total tau protein

DOI: 10.3233/JAD-170810

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1323-1332, 2018

Authors: Ding, Ding | Xiong, Yunyun | Zhao, Qianhua | Guo, Qihao | Chu, Shuguang | Chu, Winnie W.C. | Luo, Jianfeng | Liang, Xiaoniu | Zheng, Li | Hong, Zhen | Wong, Lawrence K.S. | Mok, Vincent C.T.

Article Type: Research Article

Abstract: Background: Unlike western countries, data on white matter hyperintensity (WMH) in community dwelling elderly in Asian population is very limited. Objective: To examine the relation between baseline WMH burden and the risk of incident cognitive decline in a community-based cohort with Chinese-dwelling elderly. Methods: We prospectively evaluated the incident cognitive decline for 226 participants in the Shanghai Aging Study. Baseline WMH severity was visually rated by the age-related white matter changes (ARWMC) scale based on MRI. Cox proportional hazards regression model was used to estimate the relative risk (RR) of total ARWMC scale, global ARWMC score, …presence of lacune and microbleed, for incident cognitive decline by adjusting potential confounders. Results: Forty subjects were identified with incident cognitive decline (new onset 34 mild cognitive impairment and 6 dementia) during a median duration of 6 years follow–up. The incidence of cognitive decline was 3.0 (95% confidence interval [CI] 2.2–4.1) per 100 person-years. Increasing total ARWMC scale [RR1.21 (95% CI 1.06–1.39), p  = 0.004)], confluent WMH [RR3.16 (95% CI 1.50–6.64), p  = 0.002), and presence of lacunes [RR 2.73 (95% CI 1.21–6.15)] at baseline were independent predictors of incident cognitive decline. Conclusion: Our study demonstrated that confluent WMH may increase the risk of incident cognitive decline by 3 folds in community dwelling subjects. Small vessel disease may cause heavy burden of cognitive impairment in the elderly in China. Show more

Keywords: Cognitive decline, dementia, mild cognitive impairment, small vessel disease, white matter hyperintensity

DOI: 10.3233/JAD-170876

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1333-1341, 2018

Authors: Kumfu, Sirinart | Charununtakorn, Savitree T. | Jaiwongkam, Thidarat | Chattipakorn, Nipon | Chattipakorn, Siriporn C.

Article Type: Research Article

Abstract:  Cardiac ischemia-reperfusion (I/R) injury has been shown to impair brain function. Humanin analogue (HNG) given prior to cardiac ischemia has been shown to attenuate both heart and brain mitochondrial dysfunction caused by cardiac I/R injury. In a clinical setting, patients received medical treatment for acute myocardial infarction either during or after the onset of myocardial ischemia; thus, in this study, we tested the hypothesis that the administration of HNG during cardiac I/R injury has therapeutic potential for brain protection. Thirty-six male Wistar rats were divided into two groups: a cardiac I/R group (n  = 30), and a sham group (n  = 6). …The I/R rats were then divided into five subgroups to receive: 1) vehicle; 2) HNG (84 μg/kg); 3) HNG (168 μg/kg); 4) HNG (252 μg/kg) intravenously administered during the cardiac-ischemia; and 5) HNG at 252 μg/kg given at the onset of reperfusion. At the end of treatment, brains were removed for determination of blood-brain barrier (BBB) breakdown, oxidative stress, brain mitochondrial function, brain mitochondrial dynamics, p-tau, amyloid-β (Aβ) and apoptosis. HNG at a dose of 168 and 252 μg/kg administered during ischemia, and 252 μg/kg given at the onset of reperfusion effectively attenuated the brain mitochondrial dysfunction, tau hyperphosphorylation and Aβ accumulation, and apoptosis, without reducing BBB breakdown, brain oxidative stress, or mitochondrial dynamics, caused by cardiac I/R injury. In conclusion, humanin exerted neuroprotection during induced cardiac I/R injury via improvement in brain mitochondrial function, and the reduction of Alzheimer’s disease pathology and apoptosis. Show more

Keywords: Alzheimer’s disease, brain, ischemia reperfusion injury, mitochondria, oxidative stress, pathology

DOI: 10.3233/JAD-170708

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1343-1353, 2018

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

Authors: Hall, James R. | Wiechmann, April | Johnson, Leigh A. | Edwards, Melissa | O’Bryant, Sid E.

Article Type: Research Article

Abstract: Background: Subjective cognitive complaints in cognitively normal adults have been linked to later cognitive decline and dementia. Research on the characteristics of this group has been conducted on a variety of clinical and community-based populations. The current study focuses on the rapidly expanding population of Mexican-American elders. Objective: The objective of the study is the determination of characteristics of cognitively normal Mexican-Americans with cognitive complaints. Methods: Data on 319 cognitively normal participants in a large-scale community-based study of elderly Mexican-Americans (HABLE) were analyzed comparing those with cognitive complaints with those without on clinical characteristics, affective status, …neuropsychological functioning, and proteomic markers. Results: Those expressing concern about cognitive decline scored lower on the MMSE, were more likely to have significantly more affective symptoms, higher levels of diabetic markers, poorer performance on attention and executive functioning, and a different pattern of inflammatory markers. Conclusion: Although longitudinal research is needed to determine the impact of these differences on later cognition, possible targets for early intervention with Mexican-Americans were identified. Show more

Keywords: Affective symptoms, biomarkers, Mexican-Americans, subjective cognitive complaints

DOI: 10.3233/JAD-170836

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1485-1492, 2018

Authors: Konishi, Kyoko | Joober, Ridha | Poirier, Judes | MacDonald, Kathleen | Chakravarty, Mallar | Patel, Raihaan | Breitner, John | Bohbot, Véronique D.

Article Type: Research Article

Abstract: Early detection of Alzheimer’s disease (AD) has been challenging as current biomarkers are invasive and costly. Strong predictors of future AD diagnosis include lower volume of the hippocampus and entorhinal cortex, as well as the ɛ 4 allele of the Apolipoprotein E gene (APOE) gene. Therefore, studying functions that are critically mediated by the hippocampus and entorhinal cortex, such as spatial memory, in APOE ɛ 4 allele carriers, may be key to the identification of individuals at risk of AD, prior to the manifestation of cognitive impairments. Using a virtual navigation task developed in-house, specifically designed to assess spatial versus …non-spatial strategies, the current study is the first to differentiate functional and structural differences within APOE ɛ 4 allele carriers. APOE ɛ 4 allele carriers that predominantly use non-spatial strategies have decreased fMRI activity in the hippocampus and increased atrophy in the hippocampus, entorhinal cortex, and fimbria compared to APOE ɛ 4 allele carriers who use spatial strategies. In contrast, APOE ɛ 4 allele carriers who use spatial strategies have grey matter levels comparable to non-APOE ɛ 4 allele carriers. Furthermore, in a leave-one-out analysis, grey matter in the entorhinal cortex could predict navigational strategy with 92% accuracy. Show more

Keywords: APOE, entorhinal cortex, hippocampus, spatial memory

DOI: 10.3233/JAD-170540

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1493-1507, 2018

Authors: Beach, Thomas G. | Maarouf, Chera L. | Intorcia, Anthony | Sue, Lucia I. | Serrano, Geidy E. | Lu, Ming | Joshi, Abhinay | Pontecorvo, Michael J. | Roher, Alex E.

Article Type: Research Article

Abstract: Amyloid imaging demonstrates the in vivo presence of amyloid-β (Aβ) deposits in the aging human brain but it is still unknown which structural forms and modifications of Aβ are detected. In Alzheimer’s disease, most amyloid deposits are predominantly composed of Aβ ending at amino acid residues Val40 or Ala42. It has been reported that Aβ40 is largely restricted to neuritic plaques while Aβ42 may be deposited in amyloid plaques of all types, and is often the sole component of diffuse plaques. The distinction is important as it is mainly the neuritic plaques that correlate with cognitive impairment …while diffuse plaques may be the initial type of Aβ deposited. Whether PET amyloid ligands such as florbetapir-18 F (Amyvid) are partially or wholly selective for brain deposits of Aβ40 or Aβ42 is currently unknown. We compared antemortem florbetapir PET cortical/cerebellar signal intensity (SUVr) of 55 subjects with postmortem biochemical (ELISA) measurements employing specific antibodies against Aβ40 and Aβ42 . Spearman’s univariable correlations were significant for both Aβ40 and Aβ42 , but were much stronger for Aβ42 . Multiple linear regression showed significance only for Aβ42 . These results suggest that florbetapir binds only weakly, if at all, to Aβ40 . This may be in part due to the higher likelihood for Aβ42 to be present in a β-pleated sheet tertiary structure, or to differences between Aβ40 and Aβ42 in β-pleated sheet tertiary or quaternary structure. Show more

Keywords: Alzheimer’s disease, autopsy, diagnosis, diffuse plaque, neuritic plaque

DOI: 10.3233/JAD-170762

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1509-1516, 2018

Authors: Portacolone, Elena | Johnson, Julene K. | Covinsky, Kenneth E. | Halpern, Jodi | Rubinstein, Robert L.

Article Type: Research Article

Abstract: Background: One third of older adults with cognitive impairment live alone and are at high risk for poor health outcomes. Little is known about how older adults who live alone experience the process of receiving a diagnosis of mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: The aim of this study was to understand the effects and meanings of receiving a diagnosis of MCI or AD on the lived experience of older adults living alone. Methods: This is a qualitative study of adults age 65 and over living alone with cognitive impairment. Participants’ lived experiences …were elicited through ethnographic interviews and participant observation in their homes. Using a qualitative content analysis approach, interview transcripts and fieldnotes were analyzed to identify codes and themes. Results: Twenty-nine older adults and 6 members of their social circles completed 114 ethnographic interviews. Core themes included: relief, distress, ambiguous recollections, and not knowing what to do. Participants sometimes felt uplifted and relieved by the diagnostic process. Some participants did not mention having received a diagnosis or had only partial recollections about it. Participants reported that, as time passed, they did not know what to do with regard to the treatment of their condition. Sometimes they also did not know how to prepare for a likely worsening of their condition, which they would experience while living alone. Conclusion: Findings suggest the need for more tailored care and follow-up as soon as MCI or AD is diagnosed in persons living alone. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, diagnosis, health services, residence characteristics

DOI: 10.3233/JAD-170723

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1517-1529, 2018

Authors: Paley, Elena L. | Merkulova-Rainon, Tatiana | Faynboym, Aleksandr | Shestopalov, Valery I. | Aksenoff, Igor

Article Type: Research Article

Abstract: Earlier we reported induction of neurotoxicity and neurodegeneration by tryptophan metabolites that link the metabolic alterations to Alzheimer’s disease (AD). Tryptophan is a product of the Shikimate pathway (SP). Human cells lack SP, which is found in human gut bacteria exclusively using SP to produce aromatic amino acids (AAA). This study is a first attempt toward gene-targeted analysis of human gut microbiota in AD fecal samples. The oligonucleotide primers newly-designed for this work target SP-AAA in environmental bacteria associated with human activity. Using polymerase chain reaction (PCR), we found unique gut bacterial sequence in most AD patients (18 of 20), …albeit rarely in controls (1 of 13). Cloning and sequencing AD-associated PCR products (ADPP) enables identification of Na(+)-transporting NADH: Ubiquinone reductase (NQR) in Clostridium sp. The ADPP of unrelated AD patients possess near identical sequences. NQR substrate, ubiquinone is a SP product and human neuroprotectant. A deficit in ubiquinone has been determined in a number of neuromuscular and neurodegenerative disorders. Antibacterial therapy prompted an ADPP reduction in an ADPP-positive control person who was later diagnosed with AD-dementia. We explored the gut microbiome databases and uncovered a sequence similarity (up to 97%) between ADPP and some healthy individuals from different geographical locations. Importantly, our main finding of the significant difference in the gut microbial genotypes between the AD and control human populations is a breakthrough. Show more

Keywords: Alzheimer’s disease, bacterial enzyme sequence, environmental stool samples, human gut microbiota, PCR testing

DOI: 10.3233/JAD-170764

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1531-1540, 2018

Authors: Wang, Hua | Stewart, Tessandra | Toledo, Jon B. | Ginghina, Carmen | Tang, Lu | Atik, Anzari | Aro, Patrick | Shaw, Leslie M. | Trojanowski, John Q. | Galasko, Douglas R. | Edland, Steven | Jensen, Poul H. | Shi, Min | Zhang, Jing | for The Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) features a dynamic sequence of amyloid deposition, neurodegeneration, and cognitive impairment. A significant fraction of AD brains also displays Lewy body pathology, suggesting that addition of classically Parkinson’s disease-related proteins to the AD biomarker panel may be of value. To determine whether addition of cerebrospinal fluid (CSF) total α-synuclein and its form phosphorylated at S129 (pS129) to the AD biomarker panel [Amyloid-β1-42 (Aβ42 ), tau, and phosphorylated tau (p-tau181 )] improves its performance, we examined CSF samples collected longitudinally up to 7 years as part of the Alzheimer’s Disease Neuroimaging Initiative. From 87 AD, 177 mild cognitive …impairment (MCI), and 104 age-matched healthy controls, 792 baseline and longitudinal CSF samples were tested for total α-synuclein, pS129, Aβ42 , tau, and p-tau181 . pS129, but not total α-synuclein, was weakly associated with diagnosis at baseline when t-tau/Aβ42 was included in the statistical model (β= 0.0026, p  = 0.041, 95% CI [(0.0001)–(0.005)]). CSF α-synuclein predicted Alzheimer’s Disease Assessment Scale-Cognitive (β= –0.59, p  = 0.0015, 95% CI [(–0.96)–(–0.23)]), memory (β= 0.4, p  = 0.00025, 95% CI [(0.16)–(0.59)]), and executive (0.62,<0.0001, 95% CI [(0.31)–(0.93)]) function composite scores, and progression from MCI to AD (β= 0.019, p  = 0.0011, 95% CI [(0.002)–(0.20)]). pS129 was associated with executive function (β= –2.55, p  = 0.0085, 95% CI [(–4.45)–(–0.66)]). Lower values in the mismatch between α-synuclein and p-tau181 predicted faster cognitive decline (β= 0.64, p  = 0.0012, 95% CI [(0.48)–(0.84)]). Longitudinal biomarker changes did not differ between groups, and may not reflect AD progression. The α-synuclein-p-tau181 -Mismatch could better predict longitudinal cognitive changes than classical AD markers alone, and its pathological correlates should be investigated further. Show more

Keywords: α-synuclein, Alzheimer’s disease, biomarkers, cerebrospinal fluid, mild cognitive impairment, pS129-α-synuclein

DOI: 10.3233/JAD-171013

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1541-1553, 2018

Authors: Grassi, Massimiliano | Perna, Giampaolo | Caldirola, Daniela | Schruers, Koen | Duara, Ranjan | Loewenstein, David A.

Article Type: Research Article

Abstract: Background: Available therapies for Alzheimer’s disease (AD) can only alleviate and delay the advance of symptoms, with the greatest impact eventually achieved when provided at an early stage. Thus, early identification of which subjects at high risk, e.g., with MCI, will later develop AD is of key importance. Currently available machine learning algorithms achieve only limited predictive accuracy or they are based on expensive and hard-to-collect information. Objective: The current study aims to develop an algorithm for a 3-year prediction of conversion to AD in MCI and PreMCI subjects based only on non-invasively and effectively collectable predictors. …Methods: A dataset of 123 MCI/PreMCI subjects was used to train different machine learning techniques. Baseline information regarding sociodemographic characteristics, clinical and neuropsychological test scores, cardiovascular risk indexes, and a visual rating scale for brain atrophy was used to extract 36 predictors. Leave-pair-out-cross-validation was employed as validation strategy and a recursive feature elimination procedure was applied to identify a relevant subset of predictors. Results: 16 predictors were selected from all domains excluding sociodemographic information. The best model resulted a support vector machine with radial-basis function kernel (whole sample: AUC = 0.962, best balanced accuracy = 0.913; MCI sub-group alone: AUC = 0.914, best balanced accuracy = 0.874). Conclusions: Our algorithm shows very high cross-validated performances that outperform the vast majority of the currently available algorithms, and all those which use only non-invasive and effectively assessable predictors. Further testing and optimization in independent samples will warrant its application in both clinical practice and clinical trials. Show more

Keywords: Alzheimer’s disease, clinical prediction rule, machine learning, mild cognitive impairment, personalized medicine

DOI: 10.3233/JAD-170547

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1555-1573, 2018

Authors: Tucholka, Alan | Grau-Rivera, Oriol | Falcon, Carles | Rami, Lorena | Sánchez-Valle, Raquel | Lladó, Albert | Gispert, Juan Domingo | Molinuevo, José Luis | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Gray matter changes associated with the progression of Alzheimer’s disease (AD) have been thoroughly studied. However, alterations in white matter tracts have received less attention, particularly during early or preclinical stages of the disease. Objective: To identify the structural connectivity changes across the AD continuum. Methods: We performed probabilistic tractography in a total of 183 subjects on two independent samples that include control (n  = 68) and preclinical AD individuals (n  = 28), patients diagnosed with mild cognitive impairment (MCI) due to AD (n  = 44), and AD patients (n  = 43). We compared the connectivity between groups, and …with CSF Aβ42 and tau biomarkers. Results: We observed disconnections in preclinical individuals, mainly located in the temporal lobe. This pattern of disconnection spread to the parietal and frontal lobes at the MCI stage and involved almost all the brain in AD. These findings were not driven by gray matter atrophy. Discussion: Using tractography, we were able to identify white matter changes between subsequent disease stages and, notably, also in preclinical AD. Therefore, this method may be useful for detecting early and specific brain structural changes during preclinical AD stage. Show more

Keywords: Alzheimer’s disease, biomarkers, connectivity, diffusion MRI, magnetic resonance imaging, mild cognitive impairment, preclinical stage, tractography

DOI: 10.3233/JAD-170553

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1575-1587, 2018

Authors: Fernando, W.M.A.D. Binosha | Rainey-Smith, Stephanie R. | Gardener, Samantha L. | Villemagne, Victor L. | Burnham, Samantha C. | Macaulay, S. Lance | Brown, Belinda M. | Gupta, Veer Bala | Sohrabi, Hamid R. | Weinborn, Michael | Taddei, Kevin | Laws, Simon M. | Goozee, Kathryn | Ames, David | Fowler, Christopher | Maruff, Paul | Masters, Colin L. | Salvado, Olivier | Rowe, Christopher C. | Martins, Ralph N. | For the AIBL Research Group

Article Type: Research Article

Abstract: Accumulating evidence suggests a diet high in protein and fiber may confer some protection against Alzheimer’s disease (AD). However, no human studies to-date have assessed the relationship between protein and fiber intake, and plasma and brain amyloid-β (Aβ). Consequently, this cross-sectional study, investigated the association of self-reported dietary intakes of protein and fiber, with plasma and brain Aβ burden (n  = 541, and n  = 162 respectively), in a well-characterized cohort of cognitively normal older adults, drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging. We observed 12.59 and 8.43 higher odds of ‘high’ brain Aβ burden (PiB …PET SUVR≥1.5) if protein intake fell in the lowest and middle tertile, respectively, compared to the highest tertile (p  = 0.008; p  = 0.013). Thus, in this cohort, the more protein consumed, the less likelihood of ‘high’ Aβ burden in the brain. No other significant associations were observed. The results of this study highlight the potentially protective impact of high dietary protein intake on brain Aβ burden in older adults, before objective memory decline is apparent. While longitudinal validation is required, these findings may assist in the development of dietary approaches aimed at preventing or delaying AD onset. Show more

Keywords: Alzheimer’s disease, amyloid-β, dietary fiber, dietary protein, PiB PET

DOI: 10.3233/JAD-170742

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1589-1598, 2018

Authors: Pedrinolla, Anna | Venturelli, Massimo | Fonte, Cristina | Munari, Daniele | Benetti, Maria Vittoria | Rudi, Doriana | Tamburin, Stefano | Muti, Ettore | Zanolla, Luisa | Smania, Nicola | Schena, Federico

Article Type: Research Article

Abstract: Background: Although current literature has shown that patients with Alzheimer’s disease (AD) have worse locomotion compared with healthy counterparts, no studies have focused on the efficacy of exercise training in improving gait abnormalities including biomechanics and metabolic aspects, in this population. Objective: To verify the effectiveness of exercise training (ET) on gait parameters (i.e., speed, step and stride length, single and double support, and energy cost of walking (Cw)) in patients with AD with respect to a standard cognitive treatment (CT). Methods: In this study, we included a small portion of data belonging to a larger …study (ClinicalTrials.gov number, NCT03034746). Patients with AD (Mini-Mental State Examination 22±5) were included in the study. Gait parameters and Cw were assessed at baseline and after 6 months (72 treatment sessions) of treatment. ET included 90 min of aerobic and strength training. CT included 90 min of cognitive stimuli. Results: The 16 patients assigned to ET exhibited significant improvement of Cw (–0.9±0.1 J/kg·m- 1), while differences in gait parameters were negligible. The effect on gait parameters were undetectable in the 18 patients assigned to CT (–0.2±0.5 J/kg·m-1 ). Conclusions: Data from this study showed that ET program seems effective in improving Cw in patients with AD. Interestingly, the positive effect of ET on Cw was not coupled with ameliorations of patient’s gait parameters, suggesting that the gain of metabolic aspects of locomotion were the main factors responsible for this positive result. Show more

Keywords: Dementia, energy cost of walking, physical activity, spatio-temporal gait parameters

DOI: 10.3233/JAD-170625

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1599-1609, 2018

Authors: Feng, Xueyan | Zhou, Aihong | Liu, Zhixin | Li, Fangyu | Wei, Cuibai | Zhang, Guili | Jia, Jianping

Article Type: Research Article

Abstract: Background: Delayed Matching-to-Sample Task 48 (DMS48), a brief tool measuring visual recognition memory, is valid to identify the early stage of Alzheimer’s disease (AD) in Caucasians. However, little data is available in Chinese. Objective: To develop norms and optimal cutoff points for the DMS48 in Chinese elders. Methods: A cross-sectional study was conducted in seven memory clinics from five cities across China. DMS48 was applied to 369 Chinese aged 50 or older (138 cognitively normal [CN], 112 mild cognitive impairment due to AD (MCI-A), and 119 mild AD dementia). The demographic factors which influence DMS48 scores …were investigated and the norms were established considering those factors. Receiver operating characteristic (ROC) analysis was used to determine the optimal cutoff points. Results: Age was shown to influence DMS48 scores (r  = –0.36, p  < 0.05), and we presented the age-stratified normative data for the DMS48. The optimal cutoff point is 42/43 for identifying cognitive impairment (MCI-A and AD dementia) against CN (sensitivity 97.80% and specificity 89.13%) and MCI-A against CN (sensitivity 86.60% and specificity 94.20%). A cutoff of 39/40 obtained good sensitivity (100.00%) and specificity (94.90%) in discriminating AD dementia from CN. The age-stratified optimal cutoff points for identifying MCI-A were 43/44 for individuals aged 50 to 59 years old, 42/43 for 60 to 69 years old, 41/42 for 70 to 79 years old, and 40/41 for 80 or older, respectively (sensitivity 84.80% and specificity 95.70%). Conclusion: This study proved that DMS48 is of good validation in screening MCI-A in elderly Chinese. Show more

Keywords: Alzheimer’s disease, Delayed Matching-to-Sample Task 48, dementia, mild cognitive impairment, visual memory

DOI: 10.3233/JAD-170530

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1611-1618, 2018

Authors: Ishikawa, Masatsune | Yamada, Shigeki | Yamamoto, Kazuo

Article Type: Research Article

Abstract: Background: Dilated perivascular spaces in the centrum semiovale (CSO-PVS) are closely related to small vessel disease. However, recent studies have revealed that cerebral amyloid angiopathy can cause dilation of the CSO-PVS and obstruction of interstitial fluid flow along the intramural periarterial drainage. Objective: To examine the severity and age-related prevalence of CSO-PVS through magnetic resonance imaging (MRI) and investigate their clinically relevant factors. Methods: This study included 1,060 subjects who participated in our brain program. The subjects ranged from 23 to 83 years in age and were active in society. The frequencies of the MRI abnormalities …of small vessel diseases, including CSO-PVS, were examined. The CSO-PVS severity was classified into three grades: G0, G1, G2, according to the visual rating. The subjects were divided into five age groups and their age-related frequencies were also studied. Using the clinico-laboratory data of 712 subjects, the clinically relevant factors of CSO-PVS were investigated using logistic regression analysis. Results: The frequencies of all G0 (“normal”) MRI abnormalities significantly decreased with age. A high prevalence of G2 CSO-PVS was observed (24%) in the youngest group aged≤39 years, whereas other MRI abnormalities in this group were not or rarely observed. In multivariable logistic regression analyses, G2 CSO-PVS was found to be closely associated with age, hypertension, and the estimated glomerular filtration ratio. Conclusions: This study reveals that CSO-PVS begin to develop in subjects aged less than 39 years. Age-related changes are involved. Further studies are necessary to elucidate the pathophysiological role of the CSO-PVS. Show more

Keywords: Aging, cerebral amyloid angiopathy, dementia, interstitial fluid, magnetic resonance imaging, small vessel disease, white matter

DOI: 10.3233/JAD-170755

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1619-1626, 2018

Authors: François, Mathilde | Sicsic, Jonathan | Pelletier Fleury, Nathalie

Article Type: Research Article

Abstract: Background: The impact of adverse effects of drugs for dementia on the risk of hospitalization has not been much studied despite the impact of hospitalizations on cognitive decline. Objective: To determine if the main adverse effects of cholinesterase inhibitors and memantine may be associated with excess of hospitalization and to quantify the subsequent impact on healthcare expenditures. Methods: A representative sample of the French national health insurance beneficiaries aged 65 and older and suffering from dementia were included and followed from 2007 to 2014. Binary logit models for longitudinal data (GEE estimation technique) were used to …estimate the excess of hospitalization events related to the adverse effects of anti-dementia drugs and then to derive the additional costs of hospitalizations for the public health insurance fund. Results: In total, 7,668 patients were followed, generating 111,133 individual observations over the 8-year period. Treated patients were hospitalized significantly more than non-treated patients (adjusted Odd Ratio (OR) = 1.08, 95% confidence interval (95% CI) = [1.02 to 1.13], p  = 0.004), mainly with cholinesterase inhibitors for cardiac (OR = 1.21, 95% CI = [1.01 to 1.46], p  = 0.034) and gastrointestinal events (OR = 1.43, 95% CI = [1.01–2.05], p  = 0.045), especially with rivastigmine. When extrapolated to the entire population, this corresponded to an annual additional cost of € 55,000. Conclusion: Prescription of antidementia drugs, more specifically rivastigmine, increases the risk of hospitalizations via their cardiac and gastrointestinal adverse effects and lead to additional health care expenditures. Even though these results must be confirmed, they may encourage cautious consideration of the balance between benefits and harms before a prescription is given. Show more

Keywords: Adverse effects, cholinesterase inhibitors, dementia, hospitalization, medical overuse, memantine

DOI: 10.3233/JAD-170371

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1627-1637, 2018

Authors: Redston, Mitchell R. | Hilmer, Sarah N. | McLachlan, Andrew J. | Clough, Alexander J. | Gnjidic, Danijela

Article Type: Research Article

Abstract: Background: Older people with cognitive impairment, including dementia and delirium, are high users of acute care services internationally. Potentially inappropriate medication (PIM) use may be associated with adverse outcomes, including hospital re-admission, functional disability, and mortality. Objective: This systematic review aimed to quantify and compare the prevalence of PIMs in older inpatients with and without cognitive impairment. Methods: A systematic search of observational studies was performed independently assessed by two reviewers in Embase, Medline, PsycINFO, International Pharmaceutical Abstracts, Scopus, and Informit. Articles published in English during the period January 2007–June 2017 that reported PIM prevalence in …hospital inpatients ≥ 65 years were included. PIMs were defined as the presence of polypharmacy (multiple medication use) and using implicit or explicit tools, such as the Beers criteria, and ‘Screening Tool of Older Person ’s Prescriptions ’ (STOPP). Results: 47 articles were included. In studies measuring polypharmacy (n  = 15), the prevalence of PIMs ranged from 53.2% to 89.8% and 30.4% to 97.1% for inpatients with and without cognitive impairment, respectively, and 24.0% to 80.0% when cognitive status was unreported. In studies employing explicit and implicit tools (n  = 35), the prevalence of PIMs when cognitive impairment was reported ranged from 20.6% to 80.5% using the Beers criteria, and 39.3% to 88.5% using STOPP. When cognitive status was unreported, the prevalence of PIMs ranged from 7.0% to 79.2% using the Beers criteria, and 20.0% to 63.4% using STOPP. Conclusion: Our findings suggest a high prevalence of PIMs in older inpatients with and without cognitive impairment. Future studies should investigate the impact of PIM use on patient-centered outcomes, such as functional status and quality of life, to inform enhanced acute care services. Show more

Keywords: Cognitive impairment, dementia, hospitalization, older people, polypharmacy, potentially inappropriate medications (PIMs), prevalence

DOI: 10.3233/JAD-170842

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1639-1652, 2018

Authors: Suzuki, Ayuko | Shinozaki, Jun | Yazawa, Shogo | Ueki, Yoshino | Matsukawa, Noriyuki | Shimohama, Shun | Nagamine, Takashi

Article Type: Research Article

Abstract: Background: The mental rotation task is well-known for the assessment of visuospatial function; however, it has not been used for screening of dementia patients. Objective: The aim of this study was to create a simple screening test for patients with mild cognitive impairment (MCI) and Alzheimer’s disease (AD) by focusing on non-amnestic symptoms. Methods: Age-matched healthy controls (age 75.3±6.8), patients with MCI (76.5±5.5), and AD (78.2±5.0) participated in this study. They carried out mental rotation tasks targeting geometric graphics or alphabetical characters with three rotating angles (0°, 90°, and 180°) and indicated the correct answer. Response …accuracy and reaction time were recorded along with their eye movements using an eye tracker. To quantify their visual processing strategy, the run count ratio (RC ratio) was calculated by dividing the mean number of fixations in incorrect answers by that in correct answers. Results: AD patients showed lower accuracy and longer reaction time than controls. They also showed a significantly greater number of fixation and smaller saccade amplitude than controls, while fixation duration did not differ significantly. The RC ratio was higher for AD, followed by MCI and control groups. By setting the cut-off value to 0.47 in the 180° rotating angle task, we could differentiate MCI patients from controls with a probability of 80.0%. Conclusions: We established a new screening system for dementia patients by evaluating visuospatial function. The RC ratio during a mental rotation task is useful for discriminating MCI patients from controls. Show more

Keywords: Alzheimer’s disease, cognition, early diagnosis, eye movement, mild cognitive impairment

DOI: 10.3233/JAD-170801

Citation: Journal of Alzheimer's Disease, vol. 61, no. 4, pp. 1653-1665, 2018