Browsing by Author "Mackenzie, Ian"

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    Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy
    (Wiley, 2022-10) Hopfner, Franziska; Tietz, Anja K.; Ruf, Viktoria C.; Ross, Owen A.; Koga, Shunsuke; Dickson, Dennis; Aguzzi, Adriano; Attems, Johannes; Beach, Thomas; Beller, Allison; Cheshire, William P.; van Deerlin, Vivianna; Desplats, Paula; Deuschl, Günther; Duyckaerts, Charles; Ellinghaus, David; Evsyukov, Valentin; Flanagan, Margaret Ellen; Franke, Andre; Frosch, Matthew P.; Gearing, Marla; Gelpi, Ellen; van Gerpen, Jay A.; Ghetti, Bernardino; Glass, Jonathan D.; Grinberg, Lea T.; Halliday, Glenda; Helbig, Ingo; Höllerhage, Matthias; Huitinga, Inge; Irwin, David John; Keene, Dirk C.; Kovacs, Gabor G.; Lee, Edward B.; Levin, Johannes; Martí, Maria J.; Mackenzie, Ian; McKeith, Ian; Mclean, Catriona; Mollenhauer, Brit; Neumann, Manuela; Newell, Kathy L.; Pantelyat, Alex; Pendziwiat, Manuela; Peters, Annette; Porcel, Laura Molina; Rabano, Alberto; Matěj, Radoslav; Rajput, Alex; Rajput, Ali; Reimann, Regina; Scott, William K.; Seeley , William; Selvackadunco, Sashika; Simuni, Tanya; Stadelmann, Christine; Svenningsson, Per; Thomas, Alan; Trenkwalder, Claudia; Troakes, Claire; Trojanowski, John Q.; Uitti, Ryan J.; White, Charles L.; Wszolek, Zbigniew K.; Xie, Tao; Ximelis, Teresa; Justo, Yebenes; Alzheimer’s Disease Genetics Consortium; Müller, Ulrich; Schellenberg, Gerard D.; Herms, Jochen; Kuhlenbäumer, Gregor; Höglinger, Günter; Pathology and Laboratory Medicine, School of Medicine
    Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10−6, all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.
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    Sex differences in the clinical manifestation of autosomal dominant frontotemporal dementia
    (Wiley, 2025) Memel, Molly; Staffaroni, Adam M.; Ilan-Gala, Ignacio; Garcia Castro, Jesús; Kornak, John; Tartaglia, Carmela M.; Saloner, Rowan; VandeBunte, Anna M.; Paolillo, Emily W.; Cadwallader, Claire J.; Chen, Coty; Gorno-Tempini, Maria Luisa; Mandelli, Malu; Apostolova, Liana; Graff-Radford, Neil; Litvan, Irene; Bayram, Ece; Pressman, Peter S.; Miyagawa, Toji; Mackenzie, Ian; Goldman, Jill; Darby, Richard R.; Appleby, Brian S.; Petrucelli, Len; Gendron, Tania; Heuer, Hilary W.; Forseberg, Leah K.; Rojas, Julio C.; Boeve, Brad F.; Brushaber, Nellie; Domoto-Reilly, Kimiko; Ghoshal, Nupur; Lapid, Maria; Pascual, Belen; Lee, Suzee; Ramos, Eliana Marisa; Ramanan, Vijay; Rademakers, Rosa; Rascovsky, Katya; Pantelyat, Alex; Masdeu, Joseph C.; Snyder, Allison; Boxer, Adam L.; Rosen, Howard J.; Casaletto, Kaitlin; ALLFTD Consortium; Neurology, School of Medicine
    Introduction: Sex differences are apparent in neurodegenerative diseases but have not been comprehensively characterized in frontotemporal dementia (FTD). Methods: Participants included 337 adults with autosomal dominant FTD enrolled in the ALLFTD Consortium. Clinical assessments and plasma were collected annually for up to 6 years. Linear mixed-effects models investigated how sex and disease stage are associated with longitudinal trajectories of cognition, function, and neurofilament light chain (NfL). Results: While sex differences were not apparent at asymptomatic stages, females showed more rapid declines across all outcomes in symptomatic stages compared to males. In asymptomatic participants, the association between baseline NfL and clinical trajectories was weaker in females versus males, a difference that was not present in symptomatic participants. Discussion: In genetic FTD, females show cognitive resilience in early disease stages followed by steeper clinical declines later in the disease. Baseline NfL may be a less sensitive prognostic tool for clinical progression in females with FTD-causing mutations. Highlights: Females with genetic FTD exhibit overall steeper increases in plasma neurofilament light chain (NfL) than males. Females with genetic FTD outperform NfL levels in asymptomatic stages compared to males. Once symptomatic, females with genetic FTD decline more rapidly than males. Plasma NfL is a stronger prognostic marker in asymptomatic males than females.