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Autosomal dominant dementia

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...
June 27, 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 and similarly distributed throughout mitochondrial cristae. Contrary to these parallels, both proteins form heterodimers through a bioenergetically regulated mechanism that relies on key differences in the proteins' stability as well as mutual affinity: CHCHD2 is stabilized by loss of mitochondrial membrane potential; CHCHD10 oligomerization requires CHCHD2...
July 31, 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)...
August 3, 2018: Neurology
Edouard Duchesnay, Fouad Hadj Selem, François De Guio, Mathieu Dubois, Jean-François Mangin, Marco Duering, Stefan Ropele, Reinhold Schmidt, Martin Dichgans, Hugues Chabriat, Eric Jouvent
Objective: In CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), white matter hyperintensities (WMH) are considered to result from hypoperfusion. We hypothesized that in fact the burden of WMH results from the combination of several regional populations of WMH with different mechanisms and clinical consequences. Methods: To identify regional WMH populations, we used a 4-step approach. First, we used an unsupervised principal component algorithm to determine, without a priori knowledge, the main sources of variation of the global spatial pattern of WMH...
2018: Frontiers in Neurology
Francesca Cortini, Claudia Cantoni, Chiara Villa
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of dementia in the elderly. Mutations in genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) are responsible for early-onset familial AD (EOFAD). Several pieces of evidence report that patients with rare autosomal dominant forms of AD carry a significant risk to develop seizures. However, the molecular mechanisms linking epilepsy and AD are needed to be clarified: the pathophysiology of seizures in AD may be related to an increased production of amyloid-β (Aβ) peptide or structural alterations in neurons probably due to cerebrovascular changes, neurotransmitter or cytoskeletal dysfunctions...
July 19, 2018: Seizure: the Journal of the British Epilepsy Association
Dario Saracino, Fabienne Clot, Agnès Camuzat, Vincent Anquetil, Didier Hannequin, Lucie Guyant-Maréchal, Mira Didic, Léna Guillot-Noël, Daisy Rinaldi, Morwena Latouche, Sylvie Forlani, Yassaman Ghassab, Cinzia Coppola, Giuseppe Di Iorio, Isabelle David, Eric Le Guern, Alexis Brice, Isabelle Le Ber
Valosin-containing protein (VCP) mutations are rare causes of autosomal dominant frontotemporal dementias associated with Paget's disease of bone, inclusion body myopathy, and amyotrophic lateral sclerosis. We analyzed the VCP gene in a cohort of 199 patients with frontotemporal dementia and identified 7 heterozygous mutations in unrelated families, including 3 novel mutations segregating with dementia. This expands the VCP mutation spectrum and suggests that although VCP mutations are rare (3.5% in this study), the gene should be analyzed even in absence of the full syndromic complex...
June 30, 2018: Neurobiology of Aging
Pierre N Tariot, Francisco Lopera, Jessica B Langbaum, Ronald G Thomas, Suzanne Hendrix, Lon S Schneider, Silvia Rios-Romenets, Margarita Giraldo, Natalia Acosta, Carlos Tobon, Claudia Ramos, Alejandro Espinosa, William Cho, Michael Ward, David Clayton, Michael Friesenhahn, Howard Mackey, Lee Honigberg, Sandra Sanabria Bohorquez, Kewei Chen, Trisha Walsh, Carolyn Langlois, Eric M Reiman
Introduction: Autosomal-dominant Alzheimer's disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer's disease (AD), that is, who have "preclinical" AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD...
2018: Alzheimer's & Dementia: Translational Research & Clinical Interventions
Marc Corral-Juan, Carmen Serrano-Munuera, Alberto Rábano, Daniel Cota-González, Anna Segarra-Roca, Lourdes Ispierto, Antonio Tomás Cano-Orgaz, Astrid D Adarmes, Carlota Méndez-Del-Barrio, Silvia Jesús, Pablo Mir, Victor Volpini, Ramiro Alvarez-Ramo, Ivelisse Sánchez, Antoni Matilla-Dueñas
The autosomal dominant spinocerebellar ataxias (SCAs) consist of a highly heterogeneous group of rare movement disorders characterized by progressive cerebellar ataxia variably associated with ophthalmoplegia, pyramidal and extrapyramidal signs, dementia, pigmentary retinopathy, seizures, lower motor neuron signs, or peripheral neuropathy. Over 41 different SCA subtypes have been described evidencing the high clinical and genetic heterogeneity. We previously reported a novel spinocerebellar ataxia type subtype, SCA37, linked to an 11-Mb genomic region on 1p32, in a large Spanish ataxia pedigree characterized by ataxia and a pure cerebellar syndrome distinctively presenting with early-altered vertical eye movements...
July 1, 2018: Brain: a Journal of Neurology
Asa Hatami, Chunni Zhu, Aroa Relaño-Gines, Chris Elias, Arpine Galstyan, Michael Jun, Ginger Milne, Charles R Cantor, Marie-Francoise Chesselet, Mikhail S Shchepinov
Huntington's disease (HD) is an autosomal dominant neurodegenerative disease which has no effective treatment and is characterized by psychiatric disorders, motor alterations, and dementia, with the cognitive deficits representing a devastating aspect of the disorder. Oxidative stress and elevated levels of lipid peroxidation (LPO) products are found in mouse models and patients with HD, suggesting that strategies to reduce LPO may be beneficial in HD. In contrast with traditional antioxidants, substituting hydrogen with deuterium at bis-allylic sites in polyunsaturated fatty acids (D-PUFA) decreases the rate-limiting initiation step of PUFA autoxidation, a strategy that has shown benefits in other neurodegenerative diseases...
June 22, 2018: FEBS Journal
John R Gatti, Xiaojie Zhang, Ejona Korcari, Soo Jung Lee, Nya Greenstone, Jon G Dean, Snehaa Maripudi, Michael M Wang
Vascular smooth muscle cells (SMCs) undergo a series of dramatic changes in CADASIL, the most common inherited cause of vascular dementia and stroke. NOTCH3 protein accumulates and aggregates early in CADASIL, followed by loss of mature SMCs from the media of brain arteries and marked intimal proliferation. Similar intimal thickening is seen in peripheral arterial disease, which features pathological intimal cells including proliferative, dedifferentiated, smooth muscle-like cells deficient in SMC markers. Limited studies have been performed to investigate the differentiation state and location of SMCs in brain vascular disorders...
June 22, 2018: Translational Stroke Research
Faria Zafar, Ruksana Azhu Valappil, Sam Kim, Krisztina K Johansen, Anne Lynn S Chang, James W Tetrud, Peggy S Eis, Eli Hatchwell, J William Langston, Dennis W Dickson, Birgitt Schüle
The "Iowa kindred," a large Iowan family with autosomal-dominant Parkinson's disease, has been followed clinically since the 1920s at the Mayo Clinic. In 2003, the genetic cause was determined to be a 1.7 Mb triplication of the alpha-synuclein genomic locus. Affected individuals present with an early-onset, severe parkinsonism-dementia syndrome. Here, we present a descendant of the Iowa kindred with novel, disease-associated non-motor findings of reduced heart rate variability, complete anosmia, and a rare skin condition called colloid milium...
2018: NPJ Parkinson's Disease
Elizabeth Joe, Luis D Medina, John M Ringman, Joseph O'Neill
1 H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5 T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR < 1) and 11 non-carriers as part of a comprehensive cross-sectional study of preclinical ADAD...
June 16, 2018: Brain Imaging and Behavior
Suning Ping, Xuecheng Qiu, Maria E Gonzalez-Toledo, Xiaoyun Liu, Li-Ru Zhao
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is a cerebral small vascular disease caused by NOTCH3 mutation-induced vascular smooth muscle cell (VSMC) degeneration, leading to ischemic stroke and vascular dementia. Our previous study has demonstrated that repeated treatment with a combination of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) reduces VSMC degeneration and cerebral endothelial cell (EC) damage and improves cognitive function in a mouse model of CADASIL (TgNotch3R90C)...
April 2018: Cell Transplantation
Rufus O Akinyemi, Mayowa O Owolabi, Masafumi Ihara, Albertino Damasceno, Adesola Ogunniyi, Catherine Dotchin, Stella-Maria Paddick, Julius Ogeng'o, Richard Walker, Raj N Kalaria
With increased numbers of older people a higher burden of neurological disorders worldwide is predicted. Stroke and other cerebrovascular diseases do not necessarily present with different phenotypes in Africa but their incidence is rising in tandem with the demographic change in the population. Age remains the strongest irreversible risk factor for stroke and cognitive impairment. Modifiable factors relating to vascular disease risk, diet, lifestyle, physical activity and psychosocial status play a key role in shaping the current spate of stroke related diseases in Africa...
May 25, 2018: Brain Research Bulletin
Mari Yoshida
Vascular dementia involves several mechanism of pathogenesis. Cerebral small vessel diseases play a central role in vascular dementia, including sporadic cerebral small vessel diseases, cerebral autosomal-dominant or autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL or CARASIL), cerebral amyloid angiopathy, and amyloid β-related angiitis. Although these diseases have different pathomechanisms, chronic white matter hypoperfusion contributes to development of neuronal dysfunction as a common pathway in vascular dementia...
May 2018: Brain and Nerve, Shinkei Kenkyū No Shinpo
Sejad Al-Tahan, Ebaa Al-Obeidi, Hiroshi Yoshioka, Anita Lakatos, Lan Weiss, Marjorie Grafe, Johanna Palmio, Matt Wicklund, Yadollah Harati, Molly Omizo, Bjarne Udd, Virginia Kimonis
Over fifty missense mutations in the gene coding for valosin-containing protein (VCP) are associated with a unique autosomal dominant adult-onset progressive disease associated with combinations of proximo-distal inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We report the clinical, histological, and molecular findings in four new patients/families carrying novel VCP mutations: c.474 G > A (p.M158I); c.478 G > C (p...
June 2018: Neuromuscular Disorders: NMD
Jacob W Vogel, Etienne Vachon-Presseau, Alexa Pichet Binette, Angela Tam, Pierre Orban, Renaud La Joie, Mélissa Savard, Cynthia Picard, Judes Poirier, Pierre Bellec, John C S Breitner, Sylvia Villeneuve
See Tijms and Visser (doi:10.1093/brain/awy113) for a scientific commentary on this article.Alzheimer's disease is preceded by a lengthy 'preclinical' stage spanning many years, during which subtle brain changes occur in the absence of overt cognitive symptoms. Predicting when the onset of disease symptoms will occur is an unsolved challenge in individuals with sporadic Alzheimer's disease. In individuals with autosomal dominant genetic Alzheimer's disease, the age of symptom onset is similar across generations, allowing the prediction of individual onset times with some accuracy...
June 1, 2018: Brain: a Journal of Neurology
Monica Cations, Brian Draper, Lee-Fay Low, Kylie Radford, Julian Trollor, Henry Brodaty, Perminder Sachdev, Peter Gonski, Gerald Anthony Broe, Adrienne Withall
BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD. METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia...
2018: Journal of Alzheimer's Disease: JAD
V Schubert, B Bender, M Kinzel, N Peters, T Freilinger
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) represents the most common monogenic cause of adult-onset ischemic stroke and vascular dementia. It is caused by heterozygous missense mutations in the NOTCH3 gene, encoding a transmembrane receptor protein on vascular smooth muscle cells. Classical CADASIL mutations affect conserved cysteine residues of the Notch3 protein. By contrast, the role of non-canonical genetic variation in NOTCH3, in particular of variants causing a hypomorphic Notch3 protein, is subject to an ongoing scientific debate...
June 2018: Journal of Neurology
S Chen, S He, X-H Shi, X-J Shen, K-K Liang, J-H Zhao, B-C Yan, J-W Zhang
BACKGROUND AND PURPOSE: Fatal familial insomnia (FFI) is an autosomal dominant disease due to the D178N mutation of PRNP gene coupling with homozygous methionine (Met) at codon 129. It is generally considered that D178N mutation cases with 129 M/M homozygotes present as FFI, and 129 V/V as genetic CJD. However, the frequency of 129 Met alleles in Chinese population is much higher than that in Caucasians. This study aims to investigate the clinical features and genetic characteristics of Chinese D178N mutants in this genetic context...
August 2018: Acta Neurologica Scandinavica
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