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Autosomal dominant dementia

Shan Jiang, Natalie Wen, Zeran Li, Umber Dube, Jorge Del Aguila, John Budde, Rita Martinez, Simon Hsu, Maria V Fernandez, Nigel J Cairns, Oscar Harari, Carlos Cruchaga, Celeste M Karch
Mutations in the microtubule-associated protein tau (MAPT) gene cause autosomal dominant frontotemporal lobar degeneration with tau inclusions (FTLD-tau). MAPT p.R406W carriers present clinically with progressive memory loss and neuropathologically with neuronal and glial tauopathy. However, the pathogenic events triggered by the expression of the mutant tau protein remain poorly understood. To identify the genes and pathways that are dysregulated in FTLD-tau, we performed transcriptomic analyses in induced pluripotent stem cell (iPSC)-derived neurons carrying MAPT p...
December 13, 2018: Translational Psychiatry
Karolina Machowska-Sempruch, Anna Bajer-Czajkowska, Karol Makarewicz, Karolina Zaryczańska, Adam Koryzma, Przemysław Nowacki
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetically determined disease of the cerebral vessels, characterized by recurrent ischemic strokes, dementia, and degeneration of the cerebral white matter. The condition is caused by a mutation in the NOTCH3 gene, whose product plays a great role in the development and physiology of the cardiovascular system. Magnetic resonance imaging reveals multiple hyperintensive lesions of the white matter in the T2-weighted images also in asymptomatic carriers of CADASIL and can be detected even 10-15 years prior to clinical signs...
December 10, 2018: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
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
Michael S Rafii
Alzheimer's disease (AD) pathology and early-onset dementia develop almost universally in Down syndrome (DS). AD is defined neuropathologically by the presence of extracellular plaques of aggregated amyloid β protein and intracellular neurofibrillary tangles (NFTs) of aggregated hyperphosphorylated tau protein. The development of radiolabeled positron emission tomography (PET) ligands for amyloid plaques and tau tangles enables the longitudinal assessment of the spatial pattern of their accumulation in relation to symptomatology...
December 8, 2018: Developmental Neurobiology
Suran Nethisinghe, Wei N Lim, Heather Ging, Anna Zeitlberger, Rosella Abeti, Sally Pemble, Mary G Sweeney, Robyn Labrum, Charisse Cervera, Henry Houlden, Elisabeth Rosser, Patricia Limousin, Angus Kennedy, Michael P Lunn, Kailash P Bhatia, Nicholas W Wood, John Hardy, James M Polke, Liana Veneziano, Alfredo Brusco, Mary B Davis, Paola Giunti
Spinocerebellar ataxia type 17 (SCA17) is a rare autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the TATA-box binding protein gene ( TBP ). The disease has a varied age at onset and clinical presentation. It is distinct from other SCAs for its association with dementia, psychiatric symptoms, and some patients presenting with chorea. For this reason, it is also called Huntington's disease-like 4 (HDL-4). Here we examine the distribution of SCA17 allele repeat sizes in a United Kingdom-based cohort with ataxia and find that fully penetrant pathogenic alleles are very rare (5 in 1,316 chromosomes; 0...
2018: Frontiers in Cellular Neuroscience
Wei Zhou, Dongrui Ma, Alfred Xuyang Sun, Hoang-Dai Tran, Dong-Liang Ma, Brijesh K Singh, Jin Zhou, Jinyan Zhang, Danlei Wang, Yi Zhao, Paul M Yen, Eyleen Goh, Eng-King Tan
CHCHD2 mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/ Frontotemporal dementia. In current study, we generated isogenic human stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via CRISPR-Cas9 method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with MICOS (mitochondrial inner membrane organizing system), a large protein complex maintaining mitochondria cristae...
November 29, 2018: Human Molecular Genetics
Xuan Guo, Zhe Zhao, Hongrui Shen, Bing Qi, Nan Li, Jing Hu
INTRODUCTION: Valosin-containing protein (VCP) variants that affect muscle, bone, and the nervous system are termed multisystem proteinopathy. VCP myopathy is manifested as limb-girdle weakness, distal weakness and scapuloperoneal weakness. METHODS: We reviewed clinical, genetic, and muscle biopsy data from 6 members of a family with VCP myopathy. RESULTS: Clinical features of family members were complex and included dementia, myopathy and hearing impairment...
November 29, 2018: Muscle & Nerve
Daniel Twohig, Elena Rodriguez-Vieitez, Sigrid B Sando, Guro Berge, Camilla Lauridsen, Ina Møller, Gøril R Grøntvedt, Geir Bråthen, Kalicharan Patra, Guojun Bu, Tammie L S Benzinger, Celeste M Karch, Anne Fagan, John C Morris, Randall J Bateman, Agneta Nordberg, Linda R White, Henrietta M Nielsen
Accumulating evidence demonstrating higher cerebrospinal fluid (CSF) α-synuclein (αSyn) levels and αSyn pathology in the brains of Alzheimer's disease (AD) patients suggests that αSyn is involved in the pathophysiology of AD. To investigate whether αSyn could be related to specific aspects of the pathophysiology present in both sporadic and familial disease, we quantified CSF levels of αSyn and assessed links to various disease parameters in a longitudinally followed cohort (n = 136) including patients with sporadic mild cognitive impairment (MCI) and AD, and in a cross-sectional sample from the Dominantly Inherited Alzheimer's Network (n = 142) including participants carrying autosomal dominant AD (ADAD) gene mutations and their non-mutation carrying family members...
November 26, 2018: Acta Neuropathologica Communications
Andrew E Arrant, Anthony J Filiano, Aashka R Patel, Madelyn Q Hoffmann, Nicholas R Boyle, Shreya N Kashyap, Vincent C Onyilo, Allen H Young, Erik D Roberson
Loss-of-function mutations in progranulin (GRN), most of which cause progranulin haploinsufficiency, are a major autosomal dominant cause of frontotemporal dementia (FTD). Individuals with loss-of-function mutations on both GRN alleles develop neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disorder. Progranulin is a secreted glycoprotein expressed by a variety of cell types throughout the body, including neurons and microglia in the brain. Understanding the relative importance of neuronal and microglial progranulin insufficiency in FTD pathogenesis may guide development of therapies...
November 15, 2018: Neurobiology of Disease
Jorge Rendon, Yesica Zuluaga, Lina Velilla, Jhon Ochoa, Joseph F Arboleda-Velasquez, Andrew Budson, Francisco Lopera, Yakeel T Quiroz
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common form of hereditary stroke disorder and is caused by mutations of the NOTCH3 gene. Cognitive decline in CADASIL is characterized by early impairments of attention, memory, and executive functions. Studying asymptomatic individuals with CADASIL offers a unique genetic model to understand preclinical vascular cognitive impairment and dementia. This study aimed at examine whether early preclinical physiological changes could be observed in asymptomatic individuals with CADASIL, who will go on to develop vascular cognitive impairment and dementia later in life...
November 13, 2018: Brain Research
Liam S Carroll, Thomas H Massey, Mark Wardle, Kathryn J Peall
Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei...
2018: Tremor and Other Hyperkinetic Movements
Dorota Dziewulska, Ewelina Nycz, Cecylia Rajczewska-Oleszkiewicz, Jacek Bojakowski, Dorota Sulejczak
Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a stroke and dementia syndrome with degeneration and loss of vascular smooth muscle cells (VSMCs). The disease is due to mutations in NOTCH3 playing an important role in VSMC differentiation, proliferation and apoptosis. Searching for a possible cause of VSMC dysfunction in CADASIL, we investigated morphology and proliferative activity the affected myocytes. In material from autopsy brains and skin-muscle biopsies of patients with CADASIL diagnosis, assessment of VSMCs in arterial vessels at the level of light and electron microscopy was performed...
November 6, 2018: Neuropathology: Official Journal of the Japanese Society of Neuropathology
Diana L Price, Maya A Koike, Asma Khan, Wolfgang Wrasidlo, Edward Rockenstein, Eliezer Masliah, Douglas Bonhaus
Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies...
November 1, 2018: Scientific Reports
Anna Bersano, Gloria Bedini, Hugh Stephen Markus, Paolo Vitali, Enrico Colli-Tibaldi, Franco Taroni, Cinzia Gellera, Silvia Baratta, Lorena Mosca, Paola Carrera, Maurizio Ferrari, Cristina Cereda, Gaetano Grieco, Silvia Lanfranconi, Franca Mazucchelli, Davide Zarcone, Maria Luisa De Lodovici, Giorgio Bono, Giorgio Battista Boncoraglio, Eugenio Agostino Parati, Maria Vittoria Calloni, Patrizia Perrone, Bianca Maria Bordo, Cristina Motto, Elio Agostoni, Alessandro Pezzini, Alessandro Padovani, Giuseppe Micieli, Anna Cavallini, Graziella Molini, Francesco Sasanelli, Maria Sessa, Giancarlo Comi, Nicoletta Checcarelli, Massimo Carmerlingo, Manuel Corato, Simona Marcheselli, Laura Fusi, Giampiero Grampa, Davide Uccellini, Simone Beretta, Carlo Ferrarese, Barbara Incorvaia, Carlo Sebastiano Tadeo, Laura Adobbati, Vincenzo Silani, Giuseppe Faragò, Nadia Trobia, Caspar Grond-Ginsbach, Livia Candelise
BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease, caused by NOTCH3 gene mutations. The aim of our study was to identify clinical and neuroradiological features which would be useful in identifying which patients presenting with lacunar stroke and TIA are likely to have CADASIL. METHODS: Patients with lacunar stroke or TIA were included in the present study...
December 2018: Journal of Neurology
Stephan Müller, Oliver Preische, Hamid R Sohrabi, Susanne Gräber, Mathias Jucker, John M Ringman, Ralph N Martins, Eric McDade, Peter R Schofield, Bernardino Ghetti, Martin Rossor, Nick N Fox, Neill R Graff-Radford, Johannes Levin, Adrian Danek, Jonathan Vöglein, Stephen Salloway, Chengjie Xiong, Tammie Benzinger, Virginia Buckles, Colin L Masters, Reisa Sperling, Randall J Bateman, John C Morris, Christoph Laske
INTRODUCTION: Little is known about effects of physical activity (PA) in genetically driven early-onset autosomal dominant Alzheimer's disease (AD). METHODS: A total of 372 individuals participating at the Dominantly Inherited Alzheimer Network study were examined to evaluate the cross-sectional relationship of PA with cognitive performance, functional status, cognitive decline, and AD biomarkers in cerebrospinal fluid. Mutation carriers were categorized as high or low exercisers according to WHO recommendations...
September 21, 2018: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
A Lunati, S Lesage, A Brice
The cause of Parkinson's disease (PD) remains unknown in most patients. Since 1997, with the first genetic mutation known to cause PD described in SNCA gene, many other genes with Mendelian inheritance have been identified. We summarize genetic, clinical and neuropathological findings related to the 27 genes reported in the literature since 1997, associated either with autosomal dominant (AD): LRRK2, SNCA, VPS35, GCH1, ATXN2, DNAJC13, TMEM230, GIGYF2, HTRA2, RIC3, EIF4G1, UCHL1, CHCHD2, and GBA; or autosomal recessive (AR) inheritance: PRKN, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, DNAJC6, SYNJ1, SPG11, VPS13C, PODXL, and PTRHD1; or an X-linked transmission: RAB39B...
September 20, 2018: Revue Neurologique
Miguel Ángel Araque Caballero, Marc Suárez-Calvet, Marco Duering, Nicolai Franzmeier, Tammie Benzinger, Anne M Fagan, Randall J Bateman, Clifford R Jack, Johannes Levin, Martin Dichgans, Mathias Jucker, Celeste Karch, Colin L Masters, John C Morris, Michael Weiner, Martin Rossor, Nick C Fox, Jae-Hong Lee, Stephen Salloway, Adrian Danek, Alison Goate, Igor Yakushev, Jason Hassenstab, Peter R Schofield, Christian Haass, Michael Ewers
White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease...
October 1, 2018: Brain: a Journal of Neurology
Jake Plewa, Abhilasha Surampalli, Marie Wencel, Merit Milad, Sandra Donkervoort, Vincent J Caiozzo, Namita Goyal, Tahseen Mozaffar, Virginia Kimonis
Inclusion body myopathy (IBM) associated with Paget disease of the bone and frontotemporal dementia or IBMPFD is an autosomal dominant degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. We aim to establish a detailed clinical phenotype of VCP disease amongst 35 (28 affected individuals, 7 presymptomatic gene carriers) individuals versus 14 unaffected first-degree relatives in 14 families to establish useful biomarkers for IBMPFD and identify the most meaningful tests for monitoring disease progression in future clinical trials...
September 2018: Neuromuscular Disorders: NMD
Xiaoping Huang, Beverly P Wu, Diana Nguyen, Yi-Ting Liu, Melika Marani, Jürgen Hench, Paule Bénit, Vera Kozjak-Pavlovic, Pierre Rustin, Stephan Frank, Derek P Narendra
Mutations in paralogous mitochondrial proteins CHCHD2 and CHCHD10 cause autosomal dominant Parkinson Disease (PD) and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia (ALS/FTD), respectively. Using newly generated CHCHD2, CHCHD10 and CHCHD2/10 double knockout cell lines, we find that the proteins are partially functionally redundant, similarly distributed throughout the mitochondrial cristae, and form heterodimers. Unexpectedly, we also find that CHCHD2/CHCHD10 heterodimerization increases in response to mitochondrial stress...
November 15, 2018: Human Molecular Genetics
Irene de Boer, Anine H Stam, Linde Buntinx, Ronald Zielman, Iris van der Steen, Arn M J M van den Maagdenberg, Eelco J P de Koning, Michel D Ferrari, Jan N de Hoon, Gisela M Terwindt
OBJECTIVE: We aimed to evaluate the role of endothelial-dependent and endothelial-independent vascular reactivity in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), both cerebral small vessel diseases are considered models for stroke, vascular dementia, and migraine. METHODS: RVCL-S (n = 18) and CADASIL (n = 23) participants with TREX1 and NOTCH3 mutations, respectively, were compared with controls matched for age, body mass index, and sex (n = 26)...
September 4, 2018: Neurology
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