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Neurobiology of Aging

Estrella Gómez-Tortosa, Yalda Baradaran-Heravi, Valentina González Alvarez, María José Sainz, Cristina Prieto-Jurczynska, Rosa Guerrero-López, Pablo Agüero Rabes, Christine Van Broeckhoven, Julie van der Zee, Alberto Rábano Gutiérrez
Frontotemporal lobar degeneration caused by GRN mutations is mainly associated with a TDP-43 type A proteinopathy. We present a family with autosomal dominant frontotemporal lobar degeneration caused by a novel GRN nonsense mutation (c.5G>A: p.Trp2*) in which the proband's brain also showed prominent glial tauopathy consistent with an aging-related tau astrogliopathy. Astrocytic tauopathy, 4R(+) and 3R(-) immunoreactive, was characterized by thorn-shaped astrocytes present in subpial, subependymal, and perivascular areas, and in gray matter; plus granular or fuzzy tau immunoreactivity in astrocytic processes in gray matter, either solitary or clustered in different regions...
November 20, 2018: Neurobiology of Aging
Rishika Kaja, Stephanie M Reyes, Heidi C Rossetti, E Sherwood Brown
Prior research suggests that telomere length is a biomarker of cognitive aging; however, literature has demonstrated conflicting findings to date. The present study uses data from the Dallas Heart Study, N = 2606, to assess the association between telomere length and cognitive ability on the Montreal Cognitive Assessment. The data do not support a relationship between telomere length and general cognitive functioning, (β = 0.016, SE = 0.31, p = 0.407). The data further replicate the negative findings within current literature...
November 20, 2018: Neurobiology of Aging
Cornelis Blauwendraat, Olga Pletnikova, Joshua T Geiger, Natalie A Murphy, Yevgeniya Abramzon, Gay Rudow, Adamantios Mamais, Marya S Sabir, Barbara Crain, Sarah Ahmed, Liana S Rosenthal, Catherine C Bakker, Faraz Faghri, Ruth Chia, Jinhui Ding, Ted M Dawson, Alexander Pantelyat, Marilyn S Albert, Mike A Nalls, Susan M Resnick, Luigi Ferrucci, Mark R Cookson, Argye E Hillis, Juan C Troncoso, Sonja W Scholz
Molecular genetic research provides unprecedented opportunities to examine genotype-phenotype correlations underlying complex syndromes. To investigate pathogenic mutations and genotype-phenotype relationships in diverse neurodegenerative conditions, we performed a rare variant analysis of damaging mutations in autopsy-confirmed neurodegenerative cases from the Johns Hopkins Brain Resource Center (n = 1243 patients). We used NeuroChip genotyping and C9orf72 hexanucleotide repeat analysis to rapidly screen our cohort for disease-causing mutations...
November 17, 2018: Neurobiology of Aging
Robert A Whittington, László Virág, Maud Gratuze, Hilana Lewkowitz-Shpuntoff, Mehdi Cheheltanan, Franck Petry, Isabelle Poitras, Françoise Morin, Emmanuel Planel
Preclinical studies have shown that anesthesia might accelerate the clinical progression of Alzheimer's disease (AD) and can have an impact on tau pathology, a hallmark of AD. Although benzodiazepines have been suggested to increase the risk of incident dementia, their impact on tau pathology in vivo is unknown. We thus examined the impact of midazolam, a benzodiazepine that is often administered perioperatively as an anxiolytic, on tau hyperphosphorylation in nontransgenic and in hTau mice, the latter a model of AD-like tau pathology...
November 8, 2018: Neurobiology of Aging
Jinyoung Youn, Chung Lee, Eungseok Oh, Jinse Park, Ji Sun Kim, Hee-Tae Kim, Jin Whan Cho, Woong-Yang Park, Wooyoung Jang, Chang-Seok Ki
Early-onset Parkinson's disease (EOPD) can be linked to different genetic backgrounds depending on the disease characteristics. In Korean patients with EOPD, however, only 5 PARK genes have been tested. We recruited 70 patients with EOPD from 4 hospitals in Korea, and 12 PARK genes were screened via multigene panel sequencing. Large insertions or deletions were confirmed by multiplex ligation-dependent probe amplification. We found 20 rare variants (2 in SNCA, 2 in PRKN, 6 in LRRK2, 3 in PINK1, 1 in DJ1, 4 in FBX07, 1 in HTRA2, and 1 in EIG4G1) in 20 subjects regardless of heterogeneity...
November 7, 2018: Neurobiology of Aging
Jogender Mehla, Sean G Lacoursiere, Valerie Lapointe, Bruce L McNaughton, Robert J Sutherland, Robert J McDonald, Majid H Mohajerani
Saito et al developed a novel amyloid precursor protein (APP) knock-in mouse model (APPNL-G-F ) for Alzheimer's disease (AD) to overcome the problem of overexpression of APP in available transgenic mouse models. However, this new mouse model for AD is not fully characterized age-dependently with respect to behavioral and biochemical changes. Therefore, in the present study, we performed an age-dependent behavioral and biochemical characterization of this newly developed mouse model. Here, we used 3-, 6-, 9-, and 12-month-old APPNL-G-F and C57BL/6J mice...
November 5, 2018: Neurobiology of Aging
Eliana Marisa Ramos, Christos Koros, Deepika Reddy Dokuru, Victoria Van Berlo, Christos Kroupis, Kevin Wojta, Qing Wang, Nikolaos Andronas, Stavroula Matsi, Ion N Beratis, Alden Y Huang, Suzee E Lee, Anastasios Bonakis, Chryseis Florou-Hatziyiannidou, Stella Fragkiadaki, Dionysia Kontaxopoulou, Dimitrios Agiomyrgiannakis, Vasiliki Kamtsadeli, Niki Tsinia, Vasiliki Papastefanopoulou, Maria Stamelou, Bruce L Miller, Leonidas Stefanis, John D Papatriantafyllou, Sokratis G Papageorgiou, Giovanni Coppola
Frontotemporal dementia (FTD) is a heterogeneous group of neurodegenerative syndromes associated with several causative and susceptibility genes. Herein, we aimed to determine the incidence of the most common causative dementia genes in a cohort of 118 unrelated Greek FTD spectrum patients. We also screened for novel possible disease-associated variants in additional 21 genes associated with FTD or amyotrophic lateral sclerosis. Pathogenic or likely pathogenic variants were identified in 16 cases (13.6%). These included repeat expansions in C9orf72 and loss-of-function GRN variants, and likely pathogenic variants in TARDBP, MAPT, and PSEN1...
November 3, 2018: Neurobiology of Aging
Lianteng Zhi, Qi Qin, Tanziyah Muqeem, Erin L Seifert, Wencheng Liu, Sushuang Zheng, Chenjian Li, Hui Zhang
Mutations and deletions in PTEN-induced kinase 1 (PINK1) cause autosomal recessive Parkinson's disease (PD), the second most common neurodegenerative disorder. PINK1 is a nuclear-genome encoded Ser/Thr kinase in mitochondria. PINK1 deletion was reported to affect dopamine (DA) levels in the striatum and mitochondrial functions but with conflicting results. The role of PINK1 in mitochondrial function and in PD pathogenesis remains to be elucidated thoroughly. In this study, we measured DA release using fast-scan cyclic voltammetry in acute striatal slices from both PINK1 knockout (KO) and wild-type (WT) mice at different ages...
November 2, 2018: Neurobiology of Aging
Jeroen G J van Rooij, Lieke H H Meeter, Shami Melhem, Diana A T Nijholt, Tsz Hang Wong, Annemieke Rozemuller, Andre G Uitterlinden, Joyce G van Meurs, John C van Swieten
Knowledge about the molecular mechanisms driving Alzheimer's disease (AD) is still limited. To learn more about AD biology, we performed whole transcriptome sequencing on the hippocampus of 20 AD cases and 10 age- and sex-matched cognitively healthy controls. We observed 2716 differentially expressed genes, of which 48% replicated in a second data set of 84 AD cases and 33 controls. We used an integrative network-based approach for combining transcriptomic and protein-protein interaction data to find differentially expressed gene modules that may reflect key processes in AD biology...
October 29, 2018: Neurobiology of Aging
Boris-Stephan Rauchmann, Thomas Schneider-Axmann, Panagiotis Alexopoulos, Robert Perneczky
TREM2 was suggested to be an important regulator of microglia during neurodegeneration, but previous studies report conflicting results in relation to soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) when using clinical criteria to classify Alzheimer's disease (AD). The present study explores sTREM2 CSF levels and their associations with other biomarkers and cognitive measures in a prospective AD cohort. Based on the available CSF biomarker information, 497 subjects were classified according to the 2018 National Institute on Aging-Alzheimer's Association research framework guidelines, which group biomarkers into those of amyloid-β deposition, tau pathology, and neurodegeneration...
October 25, 2018: Neurobiology of Aging
Veronika Hanko, Alexandra C Apple, Kathryn I Alpert, Kristen N Warren, Julie A Schneider, Konstantinos Arfanakis, David A Bennett, Lei Wang
Despite advances in the development of biomarkers for Alzheimer's disease (AD), accurate ante-mortem diagnosis remains challenging because a variety of neuropathologic disease states can coexist and contribute to the AD dementia syndrome. Here, we report a neuroimaging study correlating hippocampal deformity with regional AD and transactive response DNA-binding protein of 43 kDA pathology burden. We used hippocampal shape analysis of ante-mortem T1-weighted structural magnetic resonance imaging images of 42 participants from two longitudinal cohort studies conducted by the Rush Alzheimer's Disease Center...
October 25, 2018: Neurobiology of Aging
Celia Kun-Rodrigues, Tatiana Orme, Susana Carmona, Dena G Hernandez, Owen A Ross, John D Eicher, Claire Shepherd, Laura Parkkinen, Lee Darwent, Michael G Heckman, Sonja W Scholz, Juan C Troncoso, Olga Pletnikova, Ted Dawson, Liana Rosenthal, Olaf Ansorge, Jordi Clarimon, Alberto Lleo, Estrella Morenas-Rodriguez, Lorraine Clark, Lawrence S Honig, Karen Marder, Afina Lemstra, Ekaterina Rogaeva, Peter St George-Hyslop, Elisabet Londos, Henrik Zetterberg, Imelda Barber, Anne Braae, Kristelle Brown, Kevin Morgan, Claire Troakes, Safa Al-Sarraj, Tammaryn Lashley, Janice Holton, Yaroslau Compta, Vivianna Van Deerlin, Geidy E Serrano, Thomas G Beach, Suzanne Lesage, Douglas Galasko, Eliezer Masliah, Isabel Santana, Pau Pastor, Monica Diez-Fairen, Miquel Aguilar, Pentti J Tienari, Liisa Myllykangas, Minna Oinas, Tamas Revesz, Andrew Lees, Brad F Boeve, Ronald C Petersen, Tanis J Ferman, Valentina Escott-Price, Neill Graff-Radford, Nigel J Cairns, John C Morris, Stuart Pickering-Brown, David Mann, Glenda M Halliday, John Hardy, John Q Trojanowski, Dennis W Dickson, Andrew Singleton, David J Stone, Rita Guerreiro, Jose Bras
The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data...
October 24, 2018: Neurobiology of Aging
Chengyuan Mao, Herui Wang, Haiyang Luo, Shuyu Zhang, Huisha Xu, Shuo Zhang, Jared Rosenblum, Zhilei Wang, Qi Zhang, Mibo Tang, Matthew J Shepard, Xiang Wang, Yaohe Wang, Zhengping Zhuang, Changhe Shi, Yuming Xu
Previously we identified the p.Thr61Ile mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) in a Chinese family with autosomal dominant Parkinson's disease. But the mechanism is still unclear. In this study, we explored the effects of CHCHD2 p.Thr61Ile mutation in cells and its association with coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). We found that overexpression of Parkinson's disease-associated T61I mutant CHCHD2 did not produce mitochondrial dysfunction...
October 23, 2018: Neurobiology of Aging
Cindy K Barha, Teresa Liu-Ambrose, John R Best, Kristine Yaffe, Caterina Rosano
Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism may be an important source of heterogeneity seen in cognitive aging, although the specific relationship between this polymorphism and cognition remains controversial and may depend on the sex of participants. We assessed 2668 older black and white adults and fit linear mixed models to digit symbol substitution test (DSST) performance assessed in years 0 (baseline), 4, 7, and 9 to examine the interaction between sex and BDNF genotype on the intercept (i...
October 23, 2018: Neurobiology of Aging
Yuriko Katsumata, Peter T Nelson, Steven Estus, David W Fardo
The International Genomics of Alzheimer's Project (IGAP) is a consortium for characterizing the genetic landscape of Alzheimer's disease (AD). The identified and/or confirmed 19 single-nucleotide polymorphisms (SNPs) associated with AD are located on non-coding DNA regions, and their functional impacts on AD are as yet poorly understood. We evaluated the roles of the IGAP SNPs by integrating data from many resources, based on whether the IGAP SNP was (1) a proxy for a coding SNP or (2) associated with altered mRNA transcript levels...
October 23, 2018: Neurobiology of Aging
Sarah J Spencer, Bashirah Basri, Luba Sominsky, Alita Soch, Monica T Ayala, Philipp Reineck, Brant C Gibson, Ruth M Barrientos
Hippocampal microglia are vulnerable to the effects of aging, displaying a primed phenotype and hyper-responsiveness to various stimuli. We have previously shown that short-term high-fat diet (HFD) significantly impairs hippocampal- and amygdala-based cognitive function in the aged without affecting it in the young. Here, we assessed if morphological and functional changes in microglia might be responsible for this. We analyzed hippocampus and amygdala from young and aging rats that had been given three days HFD, a treatment sufficient to cause both hippocampal- and amygdala-dependent cognitive and neuroinflammatory differences in the aged...
October 23, 2018: Neurobiology of Aging
Kathy Y Liu, Julio Acosta-Cabronero, Arturo Cardenas-Blanco, Clare Loane, Alex J Berry, Matthew J Betts, Rogier A Kievit, Richard N Henson, Emrah Düzel, Robert Howard, Dorothea Hämmerer
The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinson's disease and Alzheimer's disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer-weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18-88 years)...
October 20, 2018: Neurobiology of Aging
Atahualpa Castillo-Morales, Jimena Monzón-Sandoval, Araxi O Urrutia, Humberto Gutiérrez
Different cell types have different postmitotic maintenance requirements. Nerve cells, however, are unique in this respect as they need to survive and preserve their functional complexity for the entire lifetime of the organism, and failure at any level of their supporting mechanisms leads to a wide range of neurodegenerative conditions. Whether these differences across tissues arise from the activation of distinct cell type-specific maintenance mechanisms or the differential activation of a common molecular repertoire is not known...
October 19, 2018: Neurobiology of Aging
Haoqi Sun, Luis Paixao, Jefferson T Oliva, Balaji Goparaju, Diego Z Carvalho, Kicky G van Leeuwen, Oluwaseun Akeju, Robert J Thomas, Sydney S Cash, Matt T Bianchi, M Brandon Westover
The human electroencephalogram (EEG) of sleep undergoes profound changes with age. These changes can be conceptualized as "brain age (BA)," which can be compared to chronological age to reflect the degree of deviation from normal aging. Here, we develop an interpretable machine learning model to predict BA based on 2 large sleep EEG data sets: the Massachusetts General Hospital (MGH) sleep lab data set (N = 2532; ages 18-80); and the Sleep Heart Health Study (SHHS, N = 1974; ages 40-80). The model obtains a mean absolute deviation of 7...
October 19, 2018: Neurobiology of Aging
Cynthia Anckaerts, Jaana van Gastel, Valerie Leysen, Rukun Hinz, Abdelkrim Azmi, Pascal Simoens, Disha Shah, Firat Kara, An Langbeen, Peter Bols, Charlotte Laloux, Vincent Prevot, Marleen Verhoye, Stuart Maudsley, Annemie Van der Linden
A large proportion of the population suffers from endocrine disruption, e.g., menopausal women, which might result in accelerated aging and a higher risk for developing cognitive disorders. Therefore, it is crucial to fully understand the impact of such disruptions on the brain to identify potential therapeutic strategies. Here, we show using resting-state functional magnetic resonance imaging that ovariectomy and consequent hypothalamus-pituitary-gonadal disruption result in the selective dysconnectivity of 2 discrete brain regions in mice...
October 17, 2018: Neurobiology of Aging
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