Journal of Alzheimer's Disease - Volume 65, issue 4

Authors: Finan, John D. | Udani, Shreya V. | Patel, Vimal | Bailes, Julian E.

Article Type: Review Article

Abstract: Functional outcomes after traumatic brain injury (TBI) vary widely across patients with apparently similar injuries. This variability hinders prognosis, therapy, and clinical innovation. Recently, single nucleotide polymorphism (SNPs) that influence outcome after TBI have been identified. These discoveries create opportunities to personalize therapy and stratify clinical trials. Both of these changes would propel clinical innovation in the field. This review focuses on one of most well-characterized of these SNPs, the Val66Met SNP in the brain-derived neurotrophic factor (BDNF) gene. This SNP influences neurological function in healthy subjects as well as TBI patients and patients with similar acute insults to the …central nervous system. A host of other patient-specific factors including ethnicity, age, gender, injury severity, and post-injury time point modulate this influence. These interactions confound efforts to define a simple relationship between this SNP and TBI outcomes. The opportunities and challenges associated with personalizing TBI therapy around this SNP and other similar SNPs are discussed in light of these results. Show more

Keywords: Brain-derived neurotrophic factor, precision medicine, single nucleotide polymorphism, traumatic brain injury

DOI: 10.3233/JAD-180585

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1055-1064, 2018

Authors: Serra, Laura | Gelfo, Francesca | Petrosini, Laura | Di Domenico, Carlotta | Bozzali, Marco | Caltagirone, Carlo

Article Type: Review Article

Abstract: The concept of brain, cognitive , and neural reserves has been introduced to account for the apparent discrepancies between neurological damage and clinical manifestations. However, these ideas are yet theoretical suggestions that are not completely assimilated in the clinical routine. The mechanisms of the reserves have been extensively studied in neurodegenerative pathologies, in particular in Alzheimer’s disease. Both human and animal studies addressed this topic by following two parallel pathways. The specific aim of the present review is to attempt to combine the suggestions derived from the two different research fields to deepen the knowledge about reserves. In fact, …the achievement of a comprehensive theoretical framework on reserve mechanisms is an essential step to propose well-timed interventions tailored to the clinical characteristics of patients. The present review highlights the importance of addressing three main aspects: the definition of reserve proxy measures, the interaction between reserve level and therapeutic interventions, and the specific time-window of reserve efficacy. Show more

Keywords: Alzheimer’s disease, animal studies, environmental enrichment, human studies, MRI, reserve mechanisms

DOI: 10.3233/JAD-180609

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1065-1078, 2018

Authors: Grames, Mychal S. | Dayton, Robert D. | Lu, Xiaohong | Schilke, Robert M. | Alexander, J. Steven | Orr, A. Wayne | Barmada, Sami J. | Woolard, Matthew D. | Klein, Ronald L.

Article Type: Short Communication

Abstract: A risk factor for cardiovascular disease (CVD), mutant PCSK9, was expressed in APP/PS1 mice to study the CVD-Alzheimer’s disease inter-relationship. Cholesterol levels were elevated by 5-6-fold from 3 to 13 weeks after PCSK9 gene transfer. We tested whether hypercholesterolemia would increase amyloid-β plaques at a relatively early stage of plaque deposition. Plaque burden was increased in the hippocampus of PCSK9 treated mice though the increase was modest compared to the large elevation in cholesterol. Elevating cholesterol via gene transfer could be valuable in a variety of disease models compared to making crosses with germ-line transgenic mouse models of CVD.

Keywords: Adeno-associated virus, Alzheimer’s disease, amyloid-β plaques, cardiovascular disease, gene transfer, hypercholesterolemia, PCSK9

DOI: 10.3233/JAD-180494

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1079-1086, 2018

Authors: Amen, Daniel G. | Egan, Sachit | Meysami, Somayeh | Raji, Cyrus A. | George, Noble

Article Type: Research Article

Abstract: Background: Understanding the influence of aging on the brain remains a challenge in determining its role as a risk factor for Alzheimer’s disease. Objective: To identify patterns of aging in a large neuroimaging cohort. Methods: A large psychiatric cohort of 31,227 individuals received brain SPECT at rest and during a concentration task for a total of 62,454 scans. ANOVA was done to identify the mean age trends over the course of the age range in this group, 0–105 years. A regression model in which brain SPECT regions of interest was used to predict chronological age (CA) …was then utilized to derive brain estimated age (BEA). The difference between CA and BEA was calculated to determine increased brain aging in common disorders in our sample such as depression, dementia, substance use, and anxiety. Results: Throughout the lifespan, variations in perfusion were observed in childhood, adolescence, and late life. Increased brain aging was seen in alcohol use, cannabis use, anxiety, bipolar, schizophrenia, attention-deficit/hyperactivity disorder, and in men. Conclusion: Brain SPECT can predict chronological age and this feature varies as a function of common psychiatric disorders. Show more

Keywords: Aging, alcohol use, attention-deficit/hyperactivity disorder, bipolar, brain SPECT, cannabis use, schizophrenia

DOI: 10.3233/JAD-180598

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1087-1092, 2018

Authors: Wang, Bin | Miao, Liwen | Niu, Yan | Cao, Rui | Li, Dandan | Yan, Pengfei | Guo, Hao | Yan, Tianyi | Wu, Jinglong | Xiang, Jie | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) disrupts the topological architecture of whole-brain connectivity. Minimum spanning tree (MST), which captures the most important connections in a network, has been considered an unbiased method for brain network analysis. However, the alterations in the MST of functional brain networks during the progression of AD remain unclear. Here, we performed an MST analysis to examine the alterations in functional networks among normal controls (NCs), mild cognitive impairment (MCI) patients, and AD patients. We identified substantial differences in the connections among the three groups. The maximum betweenness centrality, leaf number, and tree hierarchy of the MSTs showed significant …group differences, indicating a more star-like topology in the MCI patients and a more line-like topology in the NCs and AD patients. These findings may correspond to changes in the core of the functional brain networks. For nodal properties (degree and betweenness centrality), we determined that brain regions around the cingulate gyrus, occipital lobes, subcortex, and inferior temporal gyrus showed significant differences among the three groups and contributed to the global topological alterations. The leaf number and tree hierarchy, as well as the nodal properties, were significantly correlated with clinical features in the MCI and AD patients, which demonstrated that more star-to-line topology changes were associated with worse cognitive performance in these patients. These findings indicated that MST properties could capture slight alterations in network topology, particularly for the differences between NCs and MCI patients, and may be applicable as neuroimaging markers of the early stage of AD. Show more

Keywords: Alzheimer’s disease, brain networks, functional magnetic resonance imaging, mild cognitive impairment, minimum spanning tree

DOI: 10.3233/JAD-180603

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1093-1107, 2018

Authors: Domínguez-Prieto, Marta | Velasco, Ana | Tabernero, Arantxa | Medina, José M.

Article Type: Research Article

Abstract: Amyloid-β (Aβ) peptides, Aβ40 , Aβ42 , and recently Aβ25 - 35 , have been directly implicated in the pathogenesis of Alzheimer’s disease (AD). We have previously shown that all three peptides decrease neuronal viability, but Aβ40 also promotes synaptic disassembling. In this work, we have studied the effects of these peptides on astrocytes in primary culture and found that the three Aβ peptides were internalized by astrocytes and significantly decreased astrocyte viability, while increasing ROS production. Aβ peptide internalization is temperature-dependent, a fact that supports the idea that Aβ peptides are actively endocytosed by astrocytes. However, inhibiting caveolae formation by …methyl-beta-cyclodextrin or by silencing caveolin-1 with RNA interference did not prevent Aβ endocytosis, which suggests that Aβ peptides do not use caveolae to enter astrocytes. Conversely, inhibition of clathrin-coated vesicle formation by chlorpromazine or by silencing clathrin with RNA interference significantly decreased Aβ internalization and partially reverted the decrease of astrocyte viability caused by the presence of Aβ. These results suggest that Aβ is endocytosed by clathrin-coated vesicles in astrocytes. Aβ-loaded astrocytes, when co-incubated with non-treated astrocytes in separate wells but with the same incubation medium, promoted cell death in non-treated astrocytes; a fact that was associated with the presence of Aβ inside previously unloaded astrocytes. This phenomenon was inhibited by the presence of chlorpromazine in the co-incubation medium. These results suggest that astrocyte may perform Aβ transcytosis, a process that could play a role in the clearance of Aβ peptides from the brain to cerebrospinal fluid. Show more

Keywords: Alzheimer’s disease, amyloid-β , astrocytes, clathrin-mediated endocytosis, transcytosis

DOI: 10.3233/JAD-180332

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1109-1124, 2018

Authors: Bulk, Marjolein | Kenkhuis, Boyd | van der Graaf, Linda M. | Goeman, Jelle J. | Natté, Remco | van der Weerd, Louise

Article Type: Research Article

Abstract: The value of iron-based MRI changes for the diagnosis and staging of Alzheimer’s disease (AD) depends on an association between cortical iron accumulation and AD pathology. Therefore, this study determined the cortical distribution pattern of MRI contrast changes in cortical regions selected based on the known distribution pattern of tau pathology and investigated whether MRI contrast changes reflect the underlying AD pathology in the different lobes. T2 * -weighted MRI was performed on postmortem cortical tissue of controls, late-onset AD (LOAD), and early-onset AD (EOAD) followed by histology and correlation analyses. Combining ex vivo high-resolution MRI and histopathology revealed …that: 1) LOAD and EOAD have a different distribution pattern of AD pathological hallmarks and MRI contrast changes over the cortex, with EOAD showing more severe MRI changes; 2) per lobe, severity of AD pathological hallmarks correlates with iron accumulation, and hence with MRI. Therefore, iron-sensitive MRI sequences allow detection of the cortical distribution pattern of AD pathology ex vivo . Show more

Keywords: Amyloid, cortex, iron, magnetic resonance imaging, tau

DOI: 10.3233/JAD-180317

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1125-1137, 2018

Authors: Wong, Tsz Hang | Pottier, Cyril | Hondius, David C. | Meeter, Lieke H.H. | van Rooij, Jeroen G.J. | Melhem, Shami | The Netherlands Brain bank | van Minkelen, Rick | van Duijn, Cornelia M. | Rozemuller, Annemieke J.M. | Seelaar, Harro | Rademakers, Rosa | van Swieten, John C.

Article Type: Research Article

Abstract: Valosin-containing protein (VCP ) is involved in multiple cellular activities. Mutations in VCP lead to heterogeneous clinical presentations including inclusion body myopathy with Paget’s disease of the bone, frontotemporal dementia and amyotrophic lateral sclerosis, even in patients carrying the same mutation. We screened a cohort of 48 patients with familial frontotemporal dementia (FTD) negative for MAPT , GRN , and C9orf72 mutations for other known FTD genes by using whole exome sequencing. In addition, we carried out targeted sequencing of a cohort of 37 patients with frontotemporal lobar degeneration with Transactive response DNA-binding protein 43 (TDP-43) subtype from …the Netherlands Brain bank. Two novel (p.Thr262Ser and p.Arg159Ser) and one reported (p.Met158Val) VCP mutations in three patients with a clinical diagnosis of FTD were identified, and were absence in population-match controls. All three patients presented with behavioral changes, with additional semantic deficits in one. No signs of Paget or muscle disease were observed. Pathological examination of the patient with VCP p.Arg159Ser mutation showed numerous TDP-43 immunoreactive (IR) neuronal intranuclear inclusions (NII) and dystrophic neurites (DN), while a lower number of NII and DN were observed in the patient with the VCP p.Thr262Ser mutation. Pathological findings of both patients were consistent with FTLD-TDP subtype D. Furthermore, only rare VCP-IR NII was observed in both cases. Our study expands the clinical heterogeneity of VCP mutations carriers, and indicates that other additional factors, such as genetic modifiers, may determine the clinical phenotype. Show more

Keywords: Frontotemporal dementia, frontotemporal lobar degeneration, next generation sequencing, TDP-43, VCP gene

DOI: 10.3233/JAD-180301

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1139-1146, 2018

Authors: Benvenutto, Agnès | Giusiano, Bernard | Koric, Lejla | Gueriot, Claude | Didic, Mira | Felician, Olivier | Guye, Maxime | Guedj, Eric | Ceccaldi, Mathieu

Article Type: Research Article

Abstract: Background: Neurodegeneration biomarkers are routinely used in the diagnosis of Alzheimer’s disease (AD). Objective: To evaluate the respective contributions of two neuroimaging biomarkers, structural MRI and 18 FDG-PET, in the assessment of neurodegeneration in AD dementia. Methods: Patients with mild AD dementia diagnosed based on clinical and cerebrospinal fluid criteria and cognitively healthy subjects, from the Marseille cohort ADAge with cognitive, structural MRI and 18 FDG-PET assessments, were included. Extent of atrophy on MRI and of hypometabolism on 18 FDG-PET were individually evaluated in each patient using a voxel-based analysis on whole-brain approach and compared to …healthy subjects. Patients were divided in distinct groups according to their atrophy extent on the one hand and to their hypometabolism extent on the other, then, to their imaging profile combining the extent of the two biomarkers. Results: Fifty-two patients were included. The MMSE score was significantly lower in the “Extensive hypometabolism” group than in the “Limited hypometabolism” group (respectively 19.5/30 versus 23/30). A lower Innotest Amyloid Tau Index was associated with an extensive hypometabolism (p  = 0.04). There were more patients with low educational level in the “Extensive atrophy” group, while a higher educational level was more found in the “Limited atrophy” group (p  = 0.005). Conclusion: 18 FDG-PET hypometabolism extent is associated with the pathological processes and clinical severity of AD, while MRI atrophy seems to be influenced by the cognitive reserve. In the context of mild AD dementia, these two biomarkers of neurodegeneration are thus not interchangeable and require to be considered in combination rather than in isolation. Show more

Keywords: Alzheimer’s disease, dementia, magnetic resonance imaging, neuroimaging biomarkers, positron emission tomography imaging

DOI: 10.3233/JAD-180292

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1147-1157, 2018

Authors: Vicente, Mariane C. | Almeida, Maria C. | Bícego, Kênia C. | Carrettiero, Daniel C. | Gargaglioni, Luciane H.

Article Type: Research Article

Abstract: Besides the typical cognitive decline, patients with Alzheimer’s disease (AD) develop disorders of the respiratory system, such as sleep apnea, shortness of breath, and arrhythmias. These symptoms are aggravated with the progression of the disease. However, the cause and nature of these disturbances are not well understood. Here, we treated animals with intracerebroventricular streptozotocin (STZ, 2 mg/kg), a drug that has been described to cause Alzheimer-like behavioral and histopathological impairments. We measured ventilation ( V ̇ E ), electroencephalography, and electromyography during normocapnia, hypercapnia, and hypoxia in Wistar rats. In addition, we performed western blot analyses …for phosphorylated tau, total tau, and amyloid-β (Aβ) peptide in the locus coeruleus (LC), retrotrapezoid nucleus, medullary raphe, pre-Bötzinger/Bötzinger complex, and hippocampus, and evaluated memory and learning acquisition using the Barnes maze. STZ treatment promoted memory and learning deficits and increased the percentage of total wakefulness during normocapnia and hypercapnia due to a reduction in the length of episodes of wakefulness. CO2 -drive to breathe during wakefulness was increased by 26% in STZ-treated rats due to an enhanced tidal volume, but no changes in V ̇ E were observed in room air or hypoxic conditions. The STZ group also showed a 70% increase of Aβ in the LC and no change in tau protein phosphorylation. In addition, no alteration in body temperature was observed. Our findings suggest that AD animals present an increased sensitivity to CO2 during wakefulness, enhanced Aβ in the LC, and sleep disruption. Show more

Keywords: Breathing, chemosensitivity, dementia, hypoxia, locus coeruleus, streptozotocin

DOI: 10.3233/JAD-180397

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1159-1174, 2018

Authors: Parra-Anguita, Laura | Moreno-Cámara, Sara | López-Franco, María Dolores | Pancorbo-Hidalgo, Pedro L.

Article Type: Research Article

Abstract: Background: There are currently no questionnaires to measure the knowledge of nurses about dementia or Alzheimer’s disease care in the Spanish language. Objective: To validate the Spanish version of the Dementia Knowledge Assessment Tool 2 (DKAT2-Sp). Methods: The DKAT2 was translated into Spanish and then back-translated. The new Spanish version was validated in a sample of 361 members of the nursing staff from 24 nursing homes and a sample of 297 nursing students in Spain. Psychometric properties were assessed through an item analysis, a Rasch analysis, differential item functioning analysis, construct validity (known groups), and internal …consistency (Cronbach’s alpha). Results: The 21 items of the DKAT2-Sp fit the model well, showing a wide range of difficulty. Four items have differential items functioning between nursing professionals and students. The DKAT2-Sp shows acceptable internal consistency (Cronbach’s alpha = 0.76 for nursing professionals and 0.83 for students). Scores obtained in the known groups test were as hypothesized (Nursing home staff mean = 15.57 versus Nursing student mean = 12.85; p  < 0.0001 for mean difference), supporting construct validity. Conclusion: The DKAT2-Sp is a reliable and valid questionnaire to measure knowledge about dementia in both nursing professionals and nursing students in Spanish-speaking contexts. Show more

Keywords: Alzheimer’s disease, dementia, knowledge, nursing care, validation

DOI: 10.3233/JAD-180290

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1175-1183, 2018

Authors: Rodríguez-Cruz, Fanny | Torres-Cruz, Francisco Miguel | Monroy-Ramírez, Hugo Christian | Escobar-Herrera, Jaime | Basurto-Islas, Gustavo | Avila, Jesús | García-Sierra, Francisco

Article Type: Research Article

Abstract: Abnormal fibrillary aggregation of tau protein is a pathological condition observed in Alzheimer’s disease and other tauopathies; however, the presence and pathological significance of early non-fibrillary aggregates of tau remain under investigation. In cell and animal models expressing normal or modified tau, toxic effects altering the structure and function of several membranous organelles have also been reported in the absence of fibrillary structures; however, how these abnormalities are produced is an issue yet to be addressed. In order to obtain more insights into the mechanisms by which tau may disturb intracellular membranous elements, we transiently overexpressed human full-length tau and …several truncated tau variants in cultured neuroblastoma cells. After 48 h of transfection, either full-length or truncated tau forms produced significant fragmentation of the Golgi apparatus (GA) with no changes in cell viability. Noteworthy is that in the majority of cells exhibiting dispersion of the GA, a ring-shaped array of cortical or perinuclear microtubule (Mt) bundles was also generated under the expression of either variant of tau. In contrast, Taxol treatment of non-transfected cells increased the amount of Mt bundles but not sufficiently to produce fragmentation of the GA. Tau-induced ring-shaped Mt bundles appeared to be well-organized and stable structures because they were resistant to Nocodazole post-treatment and displayed a high level of tubulin acetylation. These results further indicate that a mechanical force generated by tau-induced Mt-bundling may be responsible for Golgi fragmentation and that the repeated domain region of tau may be the main promoter of this effect. Show more

Keywords: Alzheimer’s disease, confocal microscopy, Golgi apparatus, immunofluorescence, microtubule lattice, tau

DOI: 10.3233/JAD-180547

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1185-1207, 2018

Authors: Holden, John G. | Cosnard, Alexandre | Laurens, Brice | Asselineau, Julien | Biotti, Damien | Cubizolle, Stéphanie | Dupouy, Sandrine | Formaglio, Maıté | Koric, Lejla | Seassau, Magali | Tilikete, Caroline | Vighetto, Alain | Tison, François

Article Type: Research Article

Abstract: Saccade alterations are potential early signs of Alzheimer’s disease. However, uncertainty persists in how early and reliably automated saccade recording systems detect impairments. This multicenter pathophysiological case-control transversal study explored saccade execution in carefully diagnosed amnestic mild cognitive impairment patients fulfilling research criteria for prodromal Alzheimer’s disease (n  = 29), as compared to both aged-matched mild Alzheimer’s disease patients (n  = 23) and controls (n  = 27). Auto-coded saccades from horizontal (gap) vertical (step) stimulus elicited pro-saccades, and anti-saccade (gap) tasks were compared across the 3 groups. Mild cognitive impairment patients committed significantly more anti-saccade errors compared to controls (46.9 versus 24.3%, p … < 0.001). Conventional analyses of the auto-coded stimulus elicited saccades parameters did not distinguish the amnestic mild cognitive impairment from controls or the mild Alzheimer’s disease group. However, an offline analysis of manually coded saccade latencies, using resampling statistics did reveal subtle differences among the groups. Analysis of the manually coded data revealed that the mild Alzheimer’s disease group had a reliably larger self-corrected error-rate than in amnestic mild cognitive impairment and controls (p  = 0.003). Analysis of the manually coded saccade latencies, using more sensitive lognormal bootstrap analysis revealed a continuum, from amnestic mild cognitive impairment to mild Alzheimer’s disease, of an increased severity of impaired inhibition of stimulus elicited saccades and correct voluntary saccade initiation. Anti-saccade error rates and psychometric measures of executive and several other cognitive functions were moderately and negatively correlated. Overall, inhibitory impairments in stimulus elicited saccades, characteristic of Alzheimer’s disease, may be detected early in presumed prodromal patients using a simple, automated anti-saccade task. Show more

Keywords: Alzheimer’s disease, amnestic mild cognitive impairment, executive function, saccadic eye movements

DOI: 10.3233/JAD-180082

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1209-1223, 2018

Authors: Campbell, Jared M. | Stephenson, Matthew D. | de Courten, Barbora | Chapman, Ian | Bellman, Susan M. | Aromataris, Edoardo

Article Type: Research Article

Abstract: Background: Metformin, a first line antihyperglycemic medication, is an AMPK activator and has been hypothesized to act as a geroprotective agent. Studies on its association with various classifications of age-related cognitive decline have shown mixed results with positive and negative findings. Objective: To synthesize the best available evidence on the association of metformin-use with risk, progression, and severity of dementia. Method: Eligible research investigated the effect of metformin on dementia, Alzheimer’s disease, or any measure of cognitive impairment compared to any control group who were not receiving metformin. The initial search resulted in 862 citations from …which 14 studies (seven cohort, four cross-sectional, two RCTs, and one case control) were included. Results: Meta-analysis of three studies showed that cognitive impairment was significantly less prevalent in diabetic metformin (Odds ratio = 0.55, 95% CI 0.38 to 0.78), while six studies showed that dementia incidence was also significantly reduced (Hazard ratio = 0.76, 95% CI 0.39 to 0.88). Mini-Mental State Examination scores were not significantly affected by metformin-use, although both RCTs showed that metformin had a neuroprotective effect compared to placebo. Some studies found negative or neutral effects for metformin use by people with diabetes; the potential mechanism of metformin-induced vitamin B12 deficiency is discussed. Conclusions: Metformin should continue to be used as a first line therapy for diabetes in patients at risk of developing dementia or Alzheimer’s disease. The use of metformin by individuals without diabetes for the prevention of dementia is not supported by the available evidence. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, diabetes mellitus, meta-analysis, metformin, systematic review

DOI: 10.3233/JAD-180263

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1225-1236, 2018

Authors: Lee, Jin San | Kim, Seonwoo | Yoo, Heejin | Park, Seongbeom | Jang, Young Kyoung | Kim, Hee Jin | Kim, Ko Woon | Kim, Yeshin | Jang, Hyemin | Park, Key-Chung | Yaffe, Kristine | Yang, Jin-Ju | Lee, Jong-Min | Na, Duk L. | Seo, Sang Won

Article Type: Research Article

Abstract: Background/Objective: In this study, we investigated a long-term trajectory of brain aging (from the 20 s to over-80) in cognitively normal (CN) individuals. We further determined whether differences in sex, education years, and apolipoprotein E ε 4 status affect age-related cortical thinning. Methods: A total of 2,944 CN individuals who underwent high-resolution (3.0-Tesla) magnetic resonance imaging were included in this study. Cortical thickness was measured using a surface-based method. Multiple linear regression analyses were performed to evaluate age-related cortical thinning and related factors. Results: Compared to those in their 20 s/30 s, participants in their …40 s showed thinning primarily in the medial and lateral frontal and inferior parietal regions, and cortical thinning occurred across most of the cortices with increasing age. Notably, the precuneus, inferior temporal and lateral occipital regions were relatively spared until later in life. Male and lower education years were associated with greater cortical thinning with distinct regional specificity. Conclusion: Our findings provide an important clue to understanding the mechanism of age-related cognitive decline and new strategies for preventing the acceleration of pathological brain aging. Show more

Keywords: Alzheimer’s disease, cognitive disorders, dementia, magnetic resonance imaging

DOI: 10.3233/JAD-170537

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1237-1246, 2018

Authors: Javanshiri, Keivan | Waldö, Maria Landqvist | Friberg, Niklas | Sjövall, Fredrik | Wickerström, Karin | Haglund, Mattias | Englund, Elisabet

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most prevalent cause of dementia with vascular dementia (VaD) being second alongside with mixed AD and VaD, according to some. For some time, it has been proposed that cardiovascular disease (CaVD), hypertension, and diabetes mellitus (DM), which are known risk factors for VaD, also are associated with and contribute to the development of AD. Objective: The aim of this study was to investigate the prevalence of these proposed general risk factors, and to document presence of CaVD as evidenced from clinical records or from autopsy findings, further to correlate these with the …diagnoses AD, VaD and mixed AD-VaD (MD), respectively. Methods: Autopsy reports at the Clinical Department of Pathology in Lund from 1992–2017 were analyzed. All cases with a complete autopsy report and a neuropathologically diagnosed dementia disorder (AD, VaD, or MD) were selected on the condition of a clinical diagnosis of dementia. Clinical data were retrieved through medical records and the Swedish National Diabetes Register (NDR). A total of 268 subjects were included. Results: In AD, there was less CaVD as significantly less organ/tissue findings (p < 0.05), significantly less hypertension (p < 0.001), and likewise significantly less DM (p = 0.0014) than in VaD, with the MD group results being set between these two in all aspects studied. Conclusion: AD and VaD exhibit such different profiles of organ and vascular damage as well as of hypertension and DM that they clearly point toward different pathogenic origin with low likelihood of shared risk factors. Show more

Keywords: Alzheimer’s disease, autopsy, cardiovascular disease, dementia, dementia vascular, diabetes mellitus, hypertension, risk factors

DOI: 10.3233/JAD-180644

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1247-1258, 2018

Authors: Yuan, Hongjuan | Yang, Wenjie

Article Type: Research Article

Abstract: To evaluate whether genetically increased serum uric acid levels influence the risk of Alzheimer’s disease (AD), we used genome-wide significant single nucleotide polymorphisms for uric acid as the instrumental variables, and undertook a Mendelian randomization (MR) study to estimate the effect of uric acid on the risk of AD. The MR method prevents bias due to reverse causation (e.g., uric acid changes because of AD) and minimizes bias due to confounding of both measured and unmeasured confounders. We used the summary statistics from The International Genomics of Alzheimer’s Project Consortium that is the largest AD genome-wide association study of 74,046 …individuals of European ethnicity including 25,580 AD cases. We further performed sensitivity analyses to evaluate the assumptions of the MR method. The MR analyses did not support a causal role of genetically elevated serum uric acid on AD risk (odds ratio: 1.02, 95% confidence interval: 0.93–1.12, p  = 0.65). Sensitivity analyses, including MR-Egger regression, suggested no strong evidence of bias due to pleiotropy. In conclusion, lifelong genetically increased serum uric acid levels have no protective effect on the risk of AD. Show more

Keywords: Alzheimer’s disease, genetic correlation, Mendelian randomization, uric acid

DOI: 10.3233/JAD-180538

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1259-1265, 2018

Authors: Yumoto, Sakae | Kakimi, Shigeo | Ishikawa, Akira

Article Type: Research Article

Abstract: Increasing evidence indicates that metal-induced oxidative stress plays a pivotal role in the pathogenesis of Alzheimer’s disease (AD). Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage, was demonstrated in nuclear DNA (nDNA) in the AD brain. Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA, and aluminum (Al) has been reported to facilitate Fe-mediated oxidation. In the present study, we examined the elements contained in the nuclei of nerve cells in AD brains using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Our results demonstrated that Al and Fe were …colocalized in the nuclei of nerve cells in the AD brain. Within the nuclei, the highest levels of both Al and Fe were measured in the nucleolus. The SEM-EDS analysis also revealed the colocalization of Al and Fe in the heterochromatin and euchromatin in neuronal nuclei in the AD brain. Notably, the levels of Al and Fe in the nucleus of nerve cells in the AD brain were markedly higher than those in age-matched control brains. We hypothesize that the colocalization of Al and Fe in the nucleus of nerve cells might induce oxidative damage to nDNA and concurrently inhibit the repair of oxidatively damaged nDNA. An imbalance caused by the increase in DNA damage and the decrease in DNA repair activities might lead to the accumulation of unrepaired damaged DNA, eventually causing neurodegeneration and the development of AD. Show more

Keywords: Aluminum, Alzheimer’s disease, DNA damage, electron microscopy, energy-dispersive X-ray spectroscopy, iron, Fenton reaction, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-171108

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1267-1281, 2018

Authors: de Oliveira, Fabricio Ferreira | de Almeida, Sandro Soares | Chen, Elizabeth Suchi | Smith, Marilia Cardoso | Naffah-Mazzacoratti, Maria da Graça | Bertolucci, Paulo Henrique Ferreira

Article Type: Research Article

Abstract: Lifetime risk factors for cognitive and functional decline in Alzheimer’s disease (AD) are not fully understood, and were prospectively evaluated in patients with low mean schooling from São Paulo, Brazil. Consecutive outpatients with late-onset AD were assessed for APOE haplotypes and the following potential baseline predictors: gender, schooling, age at dementia onset, lifetime urban living and sanitary conditions, occupational complexity, cognitive and physical activities, cerebrovascular risk factors (obesity, lifetime alcohol use and smoking, length of arterial hypertension, diabetes mellitus, and a dyslipidemic profile), use of a pacemaker, creatinine clearance, body mass index, waist circumference, head traumas with unconsciousness, treated …systemic bacterial infections, amount of surgical procedures under general anesthesia, and family history of AD. Participants were followed from October 2010 to May 2017 for baseline risk factor associations with time since dementia onset for Clinical Dementia Rating and Mini-Mental State Examination score changes. For 227 patients (154 women, 119 APOE ε 4 carriers), later AD onset (mean 73.60±6.4 years-old, earlier for APOE ε 4/ε 4 carriers, p < 0.001) was the only variable hastening all endpoints, baseline creatinine clearance and lifetime alcohol use were hazardous for earlier cognitive and functional endpoints, women had earlier cognitive endpoints only, and schooling had a cumulative protective effect over later cognitive endpoints, particularly for carriers of APOE ε 4. Exclusively for carriers of APOE ε 4, head traumas with unconsciousness were hazardous for earlier cognitive endpoints, while lifetime sanitary conditions were protective regarding later cognitive endpoints. Functional and cognitive outcomes in AD represent probable interactions between effects of brain reserve and cerebral perfusion over neurodegeneration. Show more

Keywords: Aging, Alzheimer’s disease, cognition, dementia, educational status, neurodegenerative diseases, neuropsychiatry, risk factors

DOI: 10.3233/JAD-180303

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1283-1299, 2018

Authors: Buss, Stephanie S. | Padmanabhan, Jaya | Saxena, Sadhvi | Pascual-Leone, Alvaro | Fried, Peter J.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) and type 2 diabetes (T2DM) are common causes of cognitive decline among older adults and share strong epidemiological links. Distinct patterns of cortical atrophy are observed in AD and T2DM, but robust comparisons between structure-function relationships across these two disease states are lacking. Objective: To compare how atrophy within distributed brain networks is related to cognition across the spectrum of cognitive aging. Methods: The relationship between structural MRI changes and cognition was studied in 22 mild-to-moderate AD, 28 T2DM, and 27 healthy participants. Cortical thickness measurements were obtained from networks of interest …(NOIs) matching the limbic, default, and frontoparietal resting-state networks. Composite cognitive scores capturing domains of global cognition, memory, and executive function were created. Associations between cognitive scores and the NOIs were assessed using linear regression, with age as a covariate. Within-network General Linear Model (GLM) analysis was run in Freesurfer 6.0 to visualize differences in patterns of cortical atrophy related to cognitive function in each group. A secondary analysis examined hemispheric differences in each group. Results: Across all groups, cortical atrophy within the limbic NOI was significantly correlated with Global Cognition (p = 0.009) and Memory Composite (p = 0.002). Within-network GLM analysis and hemispheric analysis revealed qualitatively different patterns of atrophy contributing to cognitive dysfunction between AD and T2DM. Conclusion: Brain network atrophy is related to cognitive function across AD, T2DM, and healthy participants. Differences in cortical atrophy patterns were seen between AD and T2DM, highlighting neuropathological differences. Show more

Keywords: Alzheimer’s disease, cognitive aging, dementia, diabetes mellitus, executive function, memory disorders

DOI: 10.3233/JAD-180570

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1301-1312, 2018

Authors: Dang, Christa | Harrington, Karra D. | Lim, Yen Ying | Ames, David | Hassenstab, Jason | Laws, Simon M. | Yassi, Nawaf | Hickey, Martha | Rainey-Smith, Stephanie | Robertson, Joanne | Sohrabi, Hamid R. | Salvado, Olivier | Weinborn, Michael | Villemagne, Victor L. | Rowe, Christopher C. | Masters, Colin L. | Maruff, Paul | for the AIBL Research Group

Article Type: Research Article

Abstract: Background: Preclinical Alzheimer’s disease (AD) is defined by cerebral amyloid-β positivity (Aβ+) in cognitively normal (CN) older adults. Objective: To estimate the risk of progression to the symptomatic stages of AD due to PET Aβ+ and the extent that progression was influenced by other demographic, genetic, and clinical characteristics in a large prospective study. Methods: Fine-Gray subdistribution modeling was used to examine the risk of progression from CN to MCI/dementia due to Aβ+, APOE ɛ 4 carriage, and their interaction in the Australian Imaging, Biomarkers and Lifestyle (AIBL) flagship study of aging CN cohort (n  = 599) …over 8 years. Results: 17.7% Aβ+ and 8.1% Aβ–progressed over 8 years (OR: 2.43). Risk of progression for Aβ+ was 65–104% greater than Aβ–. Aβ+ APOE ɛ 4 carriers were at 348% greater risk than all other participants. Significant risk factors of progression in Aβ+ were age (HR: 1.05), PET SUVR (HR: 2.49) and APOE ɛ 4 carriage (HR: 2.63); only age was a significant risk factor in Aβ–(HR: 1.09). Aβ–progressors were not near the threshold for Aβ+. These relationships were not moderated by hypertension, diabetes, obesity, or stroke/TIA. Conclusion: Aβ+ is an important prognostic marker for progression from CN to MCI/dementia in older adults and APOE ɛ 4 carriage provides further predictive value in the presence of Aβ+. These data suggest that Aβ-associated clinical progression is consistent with clinical-pathological models of AD, whereas progression in the absence of elevated Aβ deposition may be the result of neuropathological processes other than AD that accumulate with age. Show more

Keywords: Alzheimer’s disease, APOE ɛ4, biomarkers, dementia, mild cognitive impairment

DOI: 10.3233/JAD-180507

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1313-1325, 2018

Authors: Ismail, Sanda | Christopher, Gary | Dodd, Emily | Wildschut, Tim | Sedikides, Constantine | Ingram, Tom A. | Jones, Roy W. | Noonan, Krist A. | Tingley, Danielle | Cheston, Richard

Article Type: Research Article

Abstract: Background: Studies with non-clinical populations show that nostalgia increases psychological resources, such as self-esteem and social connectedness. Objectives: Our objectives were to find out if the benefits of nostalgia in non-clinical populations generalize to people with dementia and if nostalgia facilitates recall of dementia-related information. Methods: All three experiments recruited participants with mild or moderate levels of dementia. Experiment 1 tested whether nostalgia (compared to control) enhances psychological resources among 27 participants. Experiment 2 used music to induce nostalgia (compared to control) in 29 participants. Experiment 3 compared recall for self-referent dementia statements among 50 participants …randomized to either a nostalgia or control condition. Findings across experiments were synthesized with integrative data analysis. Results: Nostalgia (compared to control) significantly increased self-reported social connectedness, meaning in life, self-continuity, optimism, self-esteem, and positive (but not negative) affect (Experiments 1–3). Compared to controls, nostalgic participants also recalled significantly more self-referent dementia-related information (Experiment 3). Conclusion: This series of experiments extends social psychological research with non-clinical populations into dementia care, providing evidence that nostalgia significantly enhances psychological resources. The finding that nostalgia increased recall of self-referent statements about dementia suggests that this emotion lends participants the fortitude to face the threat posed by their illness. The finding has potentially important clinical implications both for the development of reminiscence therapy and for facilitating adjustment to a diagnosis of dementia. Show more

Keywords: Alzheimer’s disease, autobiographical memory, dementia, immediate recall, psychological adaptation

DOI: 10.3233/JAD-180075

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1327-1344, 2018

Authors: Ramanan, Vijay K. | Przybelski, Scott A. | Graff-Radford, Jonathan | Castillo, Anna M. | Lowe, Val J. | Mielke, Michelle M. | Roberts, Rosebud O. | Reid, Robert I. | Knopman, David S. | Jack Jr., Clifford R. | Petersen, Ronald C. | Vemuri, Prashanthi

Article Type: Research Article

Abstract: Background: Statins have been proposed to reduce the risk of Alzheimer’s disease (AD). Objective: Assess whether long-term statin use was associated with neuroimaging biomarkers of aging and dementia. Methods: Methods: We analyzed neuroimaging biomarkers in 1,160 individuals aged 65+ from the Mayo Clinic Study of Aging, a population-based prospective longitudinal study of cognitive aging. Results: Statin-treated (5+ years of therapy) individuals had greater burden of mid-and late-life cardiovascular disease (p  < 0.001) than statin-untreated (≤3 months) individuals. Lower fractional anisotropy in the genu of the corpus callosum, an early marker of cerebrovascular disease, was associated …with long-term statin exposure (p  < 0.035). No significant associations were identified between long-term statin exposure and cerebral amyloid or tau burden, AD pattern neurodegeneration, or white matter hyperintensity burden. Conclusions: Long-term statin therapy was not associated with differences in AD biomarkers. Individuals with long-term statin exposure had worse white matter integrity in the genu of the corpus callosum, consistent with the coexistence of higher cerebrovascular risk factor burden in this group. Show more

Keywords: Alzheimer’s disease, amyloid, neurodegeneration, cerebrovascular disease, biomarkers, magnetic resonance imaging, positron emission tomography, statins, tau, white matter

DOI: 10.3233/JAD-180446

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1345-1352, 2018

Authors: Liang, Jia-Wei | Fang, Zheng-Yu | Huang, Yong | Liuyang, Zhen-yu | Zhang, Xiao-Lin | Wang, Jing-Lin | Wei, Hui | Wang, Jian-Zhi | Wang, Xiao-Chuan | Zeng, Ji | Liu, Rong

Article Type: Research Article

Abstract: Background: Weighted co-expression network analysis (WGCNA) is a powerful systems biology method to describe the correlation of gene expression based on the microarray database, which can be used to facilitate the discovery of therapeutic targets or candidate biomarkers in diseases. Objective: To explore the key genes in the development of Alzheimer’s disease (AD) by using WGCNA. Methods: The whole gene expression data GSE1297 from AD and control human hippocampus was obtained from the GEO database in NCBI. Co-expressed genes were clustered into different modules. Modules of interest were identified through calculating the correlation coefficient between the …module and phenotypic traits. GO and pathway enrichment analyses were conducted, and the central players (key hub genes) within the modules of interest were identified through network analysis. The expression of the identified key genes was confirmed in AD transgenic mice through using qRT-PCR. Results: Two modules were found to be associated with AD clinical severity, which functioning mainly in mineral absorption, NF-κ B signaling, and cGMP-PKG signaling pathways. Through analysis of the two modules, we found that metallothionein (MT), Notch2, MSX1, ADD3, and RAB31 were highly correlated with AD phenotype. Increase in expression of these genes was confirmed in aged AD transgenic mice. Conclusion: WGCNA analysis can be used to analyze and predict the key genes in AD. MT1 , MT2 , MSX1, NOTCH2 , ADD3, and RAB31 are identified to be the most relevant genes, which may be potential targets for AD therapy. Show more

Keywords: ADD3, Alzheimer’s disease, metallothionein, MSX1, Notch2, neurofibrillary tangles, RAB31, WGCNA

DOI: 10.3233/JAD-180400

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1353-1364, 2018

Authors: Tene, Oren | Hallevi, Hen | Korczyn, Amos D. | Shopin, Ludmila | Molad, Jeremy | Kirschbaum, Clemens | Bornstein, Natan M. | Shenhar-Tsarfaty, Shani | Kliper, Efrat | Auriel, Eitan | Usher, Sali | Stalder, Tobias | Ben Assayag, Einor

Article Type: Research Article

Abstract: Background and Objective: Previous studies suggest that excessive cortisol levels after stroke are associated with cognitive dysfunction. However, limited data exist regarding associations between post-stroke cortisol levels, brain abnormalities, genetic factors, and cognitive outcome. We sought to study these issues in a longitudinal stroke survivors cohort. Methods: Data from 182 cognitively intact ischemic stroke patients from the TABASCO study were available. Saliva cortisol levels (bedtime and post-awakening) and cognitive assessments were obtained on admission, and 6, 12, and 24 months thereafter. During hospitalization, patients underwent 3T MRI scans and APOE genotyping. Results: Higher bedtime cortisol levels …immediately post-stroke were associated with larger neurological deficits (p  < 0.001), brain atrophy (p  = 0.025), worse white matter integrity (p  = 0.003), and worse cognitive results up to 24 months post-stroke. These findings remained significant when adjusted for age, gender, education, smoking, stroke severity, apolipoprotein E4 (ApoE4) status, and body mass index. ApoE4 negatively modified the relation between cortisol and memory. As a group, participants who presented with high admission bedtime cortisol levels continued to present relatively elevated bedtime levels across all examined time-points, and this group had inferior memory and executive functioning scores compared to the lower cortisol group 24 months post-stroke (p  = 0.05, p  = 0.035, respectively). Post-awakening cortisol levels were not associated with neuroimaging findings or cognitive scores. Conclusions: High bedtime salivary cortisol levels post-stroke may provide information about dysregulation of diurnal HPA-axis activity under acute challenge conditions, and predict worse cognitive outcome. ApoE4 genotype might modify this association. These findings call for specific stress management interventions in stroke survivors. Show more

Keywords: ApoE4, brain atrophy, cognitive impairment, HPA axis, salivary cortisol, stroke

DOI: 10.3233/JAD-180486

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1365-1375, 2018

Authors: Koychev, Ivan | Galna, Brook | Zetterberg, Henrik | Lawson, Jennifer | Zamboni, Giovanna | Ridha, Basil H. | Rowe, James B. | Thomas, Alan | Howard, Robert | Malhotra, Paresh | Ritchie, Craig | Lovestone, Simon | Rochester, Lynn

Article Type: Research Article

Abstract: Gait disturbances are some of the earliest changes in dementia and their monitoring presents an opportunity for early diagnosis. The exact relationship between gait and well-established biomarkers of Alzheimer’s disease (AD) remains to be clarified. In this study we compared gait-related measures with cerebrospinal fluid (CSF) markers of AD pathology. We recruited seventeen participants with mild AD in a multi-site study and performed gait assessment as well as lumbar punctures to obtain CSF. CSF Aβ42 /Aβ40 and Aβ42 /Aβ38 correlated positively with measures of variability (step time and step length) in the clinic-based assessments. This was driven by …a negative relationship between gait variability and Aβ40 and Aβ38 but not Aβ42 .The amyloid ratios and gait variability measures were also associated with more severe functional impairment. We interpret these data as an indication that increasing amyloid production (i.e., increasing Aβ40 and Aβ38 ) is associated with diminishing cognitive-motor control of gait. These preliminary results suggest that the two amyloid ratios may be a marker of the earliest disturbances in the interplay between cognitive and motor control which characterize dementia. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid proteins, gait

DOI: 10.3233/JAD-180622

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1377-1383, 2018

Authors: Wang, Shanshan | He, Benhong | Hang, Weijian | Wu, NingHua | Xia, Liangtao | Wang, Xu | Zhang, Qianying | Zhou, Xinwen | Feng, Zuohua | Chen, Qingjie | Chen, Juan

Article Type: Research Article

Abstract: Background: Axonopathy is closely linked to the development of diabetic encephalopathy induced by type II diabetes (T2D). Berberine has been shown to cross the blood-brain barrier and holds promising effect for neuronal damage in diabetes. Objective: The present study investigated the protective effect and the underlying mechanism of berberine on neuronal axonopathy in both in vitro and in vivo models. Methods: High glucose/high fat diet and streptozotocin injection-induced T2D rat model was used. Berberine was administered p.o. to T2D rat model for 10 weeks. Morris water maze test, in vivo neuronal tracing, immunohistochemistry, …and western blot analysis were performed to evaluate the protective effects of berberine in T2D-induced diabetic encephalopathy rats. Primary cultured neurons were used to further explore the underlying mechanisms in vitro . Results: Berberine dramatically reduced blood glucose and serum insulin levels and alleviated insulin resistance. Berberine significantly attenuated memory impairment, axonopathy, and tau hyperphosphorylation, and also restored PI3K/Akt/GSK3β signaling pathway in T2D rats. In vitro , berberine induced an increase in the phosphorylation of PI3K/Akt as well as GSK3β in high glucose-treated primary neurons. Furthermore, berberine-induced PI3K/Akt activation also resulted in the dephosphorylation of tau protein, which could improve axonal transport impairment in high glucose-treated primary neurons. Pretreated neurons with LY294002, an inhibitor of PI3K, partially blocked berberine-inhibited tau phosphorylation and berberine-activated PI3K/Akt signaling pathway. Conclusions: Berberine exerts the protective effect against cognitive deficits by improving tau hyperphosphorylation and the axonal damage through restoring PI3K/Akt/GSK3β signaling pathway. Show more

Keywords: Axonopathy, berberine, diabetic encephalopathy, insulin, tau phosphorylation

DOI: 10.3233/JAD-180497

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1385-1400, 2018

Authors: Huan, Tao | Tran, Tran | Zheng, Jiamin | Sapkota, Shraddha | MacDonald, Stuart W. | Camicioli, Richard | Dixon, Roger A. | Li, Liang

Article Type: Research Article

Abstract: Using a non-invasive biofluid (saliva), we apply a powerful metabolomics workflow for unbiased biomarker discovery in Alzheimer’s disease (AD). We profile and differentiate Cognitively Normal (CN), Mild Cognitive Impairment (MCI), and AD groups. The workflow involves differential chemical isotope labeling liquid chromatography mass spectrometry using dansylation derivatization for in-depth profiling of the amine/phenol submetabolome. The total sample (N  = 109) was divided in to the Discovery Phase (DP) (n  = 82; 35 CN, 25 MCI, 22 AD) and a provisional Validation Phase (VP) (n  = 27; 10 CN, 10 MCI, 7 AD). In DP we detected 6,230 metabolites. Pairwise analyses confirmed biomarkers for …AD versus CN (63), AD versus MCI (47), and MCI versus CN (2). We then determined the top discriminating biomarkers and diagnostic panels. A 3-metabolite panel distinguished AD from CN and MCI (DP and VP: Area Under the Curve [AUC] = 1.000). The MCI and CN groups were best discriminated with a 2-metabolite panel (DP: AUC = 0.779; VP: AUC = 0.889). In addition, using positively confirmed metabolites, we were able to distinguish AD from CN and MCI with good diagnostic performance (AUC > 0.8). Saliva is a promising biofluid for both unbiased and targeted AD biomarker discovery and mechanism detection. Given its wide availability and convenient accessibility, saliva is a biofluid that can promote diversification of global AD biomarker research. Show more

Keywords: Alzheimer’s disease, biomarkers, liquid chromatography mass spectrometry, metabolomics, saliva, Victoria Longitudinal Study

DOI: 10.3233/JAD-180711

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1401-1416, 2018

Authors: Tariciotti, Leonardo | Casadei, Matthew | Honig, Lawrence S. | Teich, Andrew F. | McKhann II, Guy M. | Tosto, Giuseppe | Mayeux, Richard

Article Type: Research Article

Abstract: Background: Elevated total tau (tTau), 181-phosphorylated phosphorylated tau (pTau), and low amyloid-β42 (Aβ42 ) in cerebrospinal fluid (CSF) represent a diagnostic biomarker for Alzheimer’s disease (AD). Objective: The goal was to determine the overall accuracy of CSF Aβ42 , tTau, pTau, and the Aβ42 /total tau index (ATI) in a non-research, clinical setting for the diagnosis of AD. Methods: From medical records in 1,016 patients that had CSF studies for dementia over a 12-year period (2005 to 2017), we calculated the sensitivity and specificity of CSF Aβ42 , tTau, and pTau and …the ATI in relation to the final clinical diagnosis. Results: Compared with non-demented patients and patients with other dementias or mild cognitive impairment (MCI), the sensitivity and specificity of the recommended ATI and pTau cut-offs (ATI < 1.0 and pTau >61 pg/ml) for the diagnosis of AD were 0.88 and 0.72, respectively. Similar results were obtained comparing AD with non-demented patients only (0.88, 0.82) and AD with other types of dementia (0.81, 0.77). A subgroup of patients with presumed normal pressure hydrocephalus (n  = 154) were biopsied at the time of shunt placement. Using the pathological manifestations of AD as the standard, the sensitivity was 0.83 while the specificity was 0.72. Conclusions: In a non-research setting, CSF biomarkers for AD showed a high sensitivity in accordance with previous studies, but modest specificity differentiating AD from other types of dementia or MCI. This study of unselected patients provides a valid and realistic assessment of the diagnostic accuracy of these CSF biomarkers in clinical practice. Show more

Keywords: Aβ42 , accuracy, Alzheimer’s disease, CSF biomarkers, pTau, sensitivity, specificity, tTau

DOI: 10.3233/JAD-180548

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1417-1425, 2018

Authors: Crunfli, Fernanda | Mazucanti, Caio Henrique | de Moraes, Ruan Carlos Macêdo | Costa, Andressa Pereira | Rodrigues, Alice Cristina | Scavone, Cristoforo | Torrão, Andréa da Silva

Article Type: Research Article

Abstract: Sporadic Alzheimer’s disease (sAD) is associated with energy metabolism deficiency and impairment of insulin receptor (IR) signaling in the brain. In this context, low doses of intracerebroventricular (icv) injection of streptozotocin (STZ) in rodents has been used as an experimental model of sAD which leads to an insulin-resistant brain state and neurodegeneration. However, the STZ effects on brain insulin signaling-related proteins it is not appropriately elucidated. The aim of this study was to evaluate the beginning and progression of alterations in the brain IR pathway of rats after 1, 3, 5, and 7 days of STZ injection and investigate intracellular …signaling involved on STZ induced insulin resistance. We observed that STZ injection causes cognitive impairment in the animals, a temporal variation of the insulin signaling-related proteins and apoptosis cell death in the hippocampus. We also have shown that STZ causes insulin resistance and impairment on phosphoinositide 3-kinase (PI3K) activity in the Neuro-2a cells through protein kinase B (Akt) inactivation by S-nitrosylation, which could upregulate GSK3-β activity. STZ ability to cause an insulin-resistant neuron state involves NO production and ROS production which may play an important role in the mechanism linked to STZ-induced neurotoxicity. The icv injection of STZ model and STZ exposed Neuro-2a cells may be potential experimental models for assessing molecules related to the pathogenesis of sAD. Show more

Keywords: Alzheimer’s disease, Akt, insulin resistance, nitric oxide, streptozotocin

DOI: 10.3233/JAD-180284

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1427-1443, 2018

Authors: Bloch, Konstantin | Gil-Ad, Irit | Vanichkin, Alexey | Hornfeld, Shay Henry | Taler, Michal | Dar, Shira | Azarov, Dmitry | Vardi, Pnina | Weizman, Abraham

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is often associated with brain insulin resistance and peripheral metabolic dysfunctions. Recently, we developed a model of sporadic AD associated with obesity-related peripheral metabolic abnormalities in Lewis rats using intracerebroventricular administration of streptozotocin (icv-STZ). Objective: We aimed to assess the effect of intracranially grafted pancreatic islets on cognitive and peripheral metabolic dysfunctions in the icv-STZ Lewis rats. Methods: AD-like dementia associated with obesity was induced in inbred Lewis rats using a single icv-STZ. Two months after icv-STZ, syngeneic islets (100 islets per recipient) were implanted in the cranial subarachnoid …cavity of icv-STZ rats. Morris water maze and marble burying tests were used for studying cognitive and behavioral functions. Central and peripheral metabolic alterations were assessed by histological and biochemical assays. Results: The icv-STZ induced increases in food intake, body weight, and blood levels of insulin and leptin without alteration of glucose homeostasis. Grafted islets reduced body weight gain, food consumption, peripheral insulin resistance, and hyperleptinemia. Biochemical and histological analysis of the brain revealed viable grafted islets expressing insulin and glucagon. The grafted islets did not affect expression of brain insulin receptors and peripheral glucose homeostasis. Two months after islet transplantation, cognitive and behavioral functioning in transplanted rats were significantly better than the sham-operated icv-STZ rats. No significant differences in the locomotor activity between transplanted and non-transplanted icv-STZ rats were found. Conclusions: Intracranial islet transplantation attenuates cognitive decline and peripheral metabolic dysfunctions providing a novel therapeutic approach for sporadic AD associated with peripheral metabolic dysfunctions. Show more

Keywords: Alzheimer’s disease, animal models, dementia, obesity, pancreatic islet transplantation

DOI: 10.3233/JAD-180623

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1445-1458, 2018

Authors: Hedderich, Dennis M. | Spiro, Judith E. | Goldhardt, Oliver | Kaesmacher, Johannes | Wiestler, Benedikt | Yakushev, Igor | Zimmer, Claus | Boeckh-Behrens, Tobias | Grimmer, Timo

Article Type: Research Article

Abstract: Background: Volumetric quantification of structural MRI has been shown to increase the diagnostic accuracy of patients with mild cognitive impairment (MCI); however, its implementation in clinical routine is usually technically difficult and time-consuming. Objective: The purpose of this study was to investigate whether volumetric information obtained from the free and easy-to-use online tool volBrain can improve correct identification of MCI patients with Alzheimer’s disease (AD) compared to visual reading. Methods: The study cohort consisted of 27 patients with MCI due to AD (AD positive) as determined by biomarker information and 26 cognitively normal controls (CN). Three …blinded readers, 2 radiologists and 1 clinical dementia expert, assessed the patients’ MRI regarding brain atrophy and probability of underlying AD two times, without and with supporting volumetric information from volBrain. To assess diagnostic accuracy of volBrain measures alone, a simple sum score based on basic volumetric measures was developed and tested. Results: Correct patient classification by readers 1, 2, and 3 without a volumetric report was 73.6%, 77.4%, and 83.0%. With a volumetric report, correct classification increased for the radiological readers to 77.4% and 81.1%, respectively and decreased to 77.4% for reader 3. Usage of the volumetric report alone yielded the highest diagnostic accuracy of 84.9%. Diagnostic confidence increased significantly for radiological readers. Conclusion: Volumetric information from volBrain increases the radiologist’s diagnostic performance and confidence in identifying MCI patients with AD. We propose that such tools may be implemented in the routine diagnostic work-up of patients with suspected AD. Show more

Keywords: Alzheimer’s disease, magnetic resonance imaging, mild cognitive impairment, neurodegenerative disease

DOI: 10.3233/JAD-180532

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1459-1467, 2018

Authors: Garzón, Fernando | Coimbra, Débora | Parcerisas, Antoni | Rodriguez, Yamila | García, Julio Cesar | Soriano, Eduardo | Rama, Ramón

Article Type: Research Article

Abstract: Many experimental studies show that erythropoietin (EPO) has a neuroprotective action in the brain. EPO in acute and chronic neurological disorders, particularly in stroke, traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, has neuroprotective effects. We previously reported the neuroprotective effect of NeuroEPO, a low sialic form of EPO, against oxidative stress induced by glutamate excitotoxicity. In this paper, we analyze the effect of NeuroEPO against apoptosis induced by glutamate excitotoxicity in primary neuronal cultures obtained from the forebrains of Wistar rat embryos after 17 days of gestation. Excitotoxicity was induced after nine days of in vitro …culture by treatment with a culture medium containing 100μ M glutamate for 15 min. To withdraw glutamate, a new medium containing 100 ng NeuroEPO/mL was added. Apoptosis was analyzed after 24 h. Images obtained by phase contrast microscopy show that neurons treated with glutamate exhibit cell body shrinkage, loss of dendrites that do not make contact with neighboring cells, and that NeuroEPO was able to preserve the morphological characteristics of the control. Immunocytochemistry images show that the culture is essentially pure in neurons; that glutamate causes cell mortality, and that this is partially avoided when the culture medium is supplemented with NeuroEPO. Activation of intrinsic apoptotic pathways was analyzed. The decreases in Bcl-2/Bax ratio, increase in the release of cytochrome c, and in the expression and activity of caspase-3 observed in cells treated with glutamate, were restored by NeuroEPO. The results from this study show that NeuroEPO protects cortical neurons from glutamate-induced apoptosis via upregulation of Bcl-2 and inhibit glutamate-induced activation of caspase-3. Show more

Keywords: Apoptosis, erythropoietin, excitotoxicity, neurodegenerative diseases, NeuroEPO, neuroprotection

DOI: 10.3233/JAD-180668

Citation: Journal of Alzheimer's Disease, vol. 65, no. 4, pp. 1469-1483, 2018