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  • Orme, Tatiana; Hernandez, Dena; Ross, Owen A.; Kun-Rodrigues, Celia; Darwent, Lee; Shepherd, Claire E.; Parkkinen, Laura; Ansorge, Olaf; Clark, Lorraine; Honig, Lawrence S.; Marder, Karen; Lemstra, Afina; Rogaeva, Ekaterina; St. George-Hyslop, Peter; Londos, Elisabet; Zetterberg, Henrik; Morgan, Kevin; Troakes, Claire; Al-Sarraj, Safa; Lashley, Tammaryn; Holton, Janice; Compta, Yaroslau; Van Deerlin, Vivianna; Trojanowski, John Q.; Serrano, Geidy E.; Beach, Thomas G.; Lesage, Suzanne; Galasko, Douglas; Masliah, Eliezer; Santana, Isabel; Pastor, Pau; Tienari, Pentti J.; Myllykangas, Liisa; Oinas, Minna; Revesz, Tamas; Lees, Andrew; Boeve, Brad F.; Petersen, Ronald C.; Ferman, Tanis J.; Escott-Price, Valentina; Graff-Radford, Neill; Cairns, Nigel J.; Morris, John C.; Pickering-Brown, Stuart; Mann, David; Halliday, Glenda; Stone, David J.; Dickson, Dennis W.; Hardy, John; Singleton, Andrew; Guerreiro, Rita; Bras, Jose (2020)
    Dementia with Lewy bodies (DLB) is a clinically heterogeneous disorder with a substantial burden on healthcare. Despite this, the genetic basis of the disorder is not well defined and its boundaries with other neurodegenerative diseases are unclear. Here, we performed whole exome sequencing of a cohort of 1118 Caucasian DLB patients, and focused on genes causative of monogenic neurodegenerative diseases. We analyzed variants in 60 genes implicated in DLB, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, and atypical parkinsonian or dementia disorders, in order to determine their frequency in DLB. We focused on variants that have previously been reported as pathogenic, and also describe variants reported as pathogenic which remain of unknown clinical significance, as well as variants associated with strong risk. Rare missense variants of unknown significance were found in APP, CHCHD2, DCTN1, GRN, MAPT, NOTCH3, SQSTM1, TBK1 and TIA1. Additionally, we identified a pathogenic GRN p.Arg493* mutation, potentially adding to the diversity of phenotypes associated with this mutation. The rarity of previously reported pathogenic mutations in this cohort suggests that the genetic overlap of other neurodegenerative diseases with DLB is not substantial. Since it is now clear that genetics plays a role in DLB, these data suggest that other genetic loci play a role in this disease.
  • Peteri, Ulla-Kaisa; Niukkanen, Mikael; Castren, Maija L. (2019)
    To an increasing extent, astrocytes are connected with various neuropathologies. Astrocytes comprise of a heterogeneous population of cells with region- and species-specific properties. The frontal cortex exhibits high levels of plasticity that is required for high cognitive functions and memory making this region especially susceptible to damage. Aberrations in the frontal cortex are involved with several cognitive disorders, including Alzheimer's disease, Huntington's disease and frontotemporal dementia. Human induced pluripotent stem cells (iPSCs) provide an alternative for disease modeling and offer possibilities for studies to investigate pathological mechanisms in a cell type-specific manner. Patient-specific iPSC-derived astrocytes have been shown to recapitulate several disease phenotypes. Addressing astrocyte heterogeneity may provide an improved understanding of the mechanisms underlying neurodegenerative diseases.
  • Talaslahti, Tiina; Ginters, Milena; Kautiainen, Hannu; Vataja, Risto; Elonheimo, Henrik; Erkinjuntti, Timo; Suvisaari, Jaana; Lindberg, Nina; Koponen, Hannu (2021)
    Objective: To explore the criminality of patients with subsequent diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), or Lewy body dementias (LBD) in the four years preceding diagnosis. Design: Nationwide register study. Setting: Data on Finnish patients were collected from the discharge register and data on criminal offending from the police register. Research findings were compared with the same-aged general population. Participants: A total of 92,191 patients who had received a diagnosis of AD (N = 80,540), FTD (N = 1,060), and LBD (N = 10,591) between 1998 and 2015. Measurements: Incidences and types of crimes, the standardized criminality ratio (number of actual crimes per number of expected crimes), and the numbers of observed cases and person-years at risk counted in five-year age groups and separately for both genders and yearly. Results: At least one crime was committed by 1.6% of AD women and 12.8% of AD men, with corresponding figures of 5.3% and 23.5% in FTD, and 3.0% and 11.8% in LBD. The first crime was committed on average 2.7 (standard deviation 1.1) years before the diagnosis. The standardized criminality ratio was 1.85 (95% confidence interval [CI] 1.43 -2.37) in FTD women and 1.75 (95% CI 1.54-1.98) in FTD men, and in AD 1.11 (95% CI 1.04-1.17) and 1.23 (95% CI 1.20-1.27), respectively. Traffic offences and crimes against property constituted 94% of all offences. Conclusion: Criminal acts may occur several years prior to the diagnosis of dementia. If novel criminality occurs later in life, it may be associated with neurocognitive disorder.
  • Polanco, Juan Carlos; Akimov, Yevhen; Fernandes, Avinash; Briner, Adam; Hand, Gabriel Rhys; van Roijen, Marloes; Balistreri, Giuseppe; Götz, Jürgen (2022)
    The aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer's disease and other tauopathies. Tau pathology is believed to be driven by free tau aggregates and tau carried within exosome-like extracellular vesicles, both of which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. We identified ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18 as the top validated regulators that restrict tau aggre-gation initiated by both exosomal and vesicle-free tau seeds. None of our validated hits affected the uptake of either form of tau seeds, supporting the notion that they operate through a cell -autonomous mechanism downstream of the seed uptake. Lastly, validation studies with human brain tissue also revealed that several of the identified protein hits are down-regulated in the brains of Alzheimer's patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.
  • Kero, Mia; Raunio, Anna; Polvikoski, Tuomo; Tienari, Pentti J.; Paetau, Anders; Myllykangas, Liisa (2018)
    Background: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. Objective: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP-43, p62, and HPtau was studied. Methods: The population-based Vantaa 85(+) study includes all inhabitants of the city of Vantaa, who were > 85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE-staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. Results: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p <0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p <0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. Conclusion: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination.
  • Brunello, Cecilia A.; Merezhko, Maria; Uronen, Riikka-Liisa; Huttunen, Henri J. (2020)
    Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer’s disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.
  • Palmio, Johanna; Evilä, Anni; Bashir, Ayat; Norwood, Fiona; Viitaniemi, Kati; Vihola, Anna; Huovinen, Sanna; Straub, Volker; Hackman, Peter; Hirano, Michio; Bushby, Kate; Udd, Bjarne (2016)
  • Solje, Eino; Aaltokallio, Heidi; Koivumaa-Honkanen, Heli; Suhonen, Noora M.; Moilanen, Virpi; Kiviharju, Anna; Traynor, Bryan; Tienari, Pentti J.; Hartikainen, Paivi; Remes, Anne M. (2015)
    Background The C9ORF72 expansion is one of the most common genetic etiologies observed with behavioural variant frontotemporal dementia (bvFTD). Revised diagnostic criteria for bvFTD (FTDC) were recently introduced but only a few studies have evaluated the accuracy of these criteria. Objective The objective of the study was to evaluate the applicability of the FTDC criteria and assess the psychiatric history of these patients. Methods The study examined 36 patients carrying the C9ORF72 expansion and suffering from bvFTD (N = 32) or from bvFTD with motor neuron disease (bvFTD-MND, N = 4). Neuropsychological, neuropsychiatric, structural brain imaging and PET/SPECT data were evaluated. Results We found 0.75 sensitivity (SD 0.44, 95% CI 0.57-0.87) for possible bvFTD and 0.64 (SD 0.44, 95% CI 0.57-0.87) for probable bvFTD. The sensitivity was even higher in bvFTD patients without MND, i.e., 0.81 for possible bvFTD and 0.69 for probable bvFTD. PET/SPECT was normal in 17.6% of scanned patients with bvFTD. A history of psychiatric symptoms (psychotic and/or mood symptoms) was detected in 61% of cases. Conclusions The FTDC possible and probable bvFTD criteria seem to identify the majority of the C9ORF72 expansion carriers with bvFTD, even though they exhibit only a limited number of behavioral criteria but a significant amount of psychiatric symptoms. The presence of a normal PET/SPECT does not exclude the possibility the C9ORF72 associated bvFTD.
  • Deneubourg, Celine; Ramm, Mauricio; Smith, Luke J.; Baron, Olga; Singh, Kritarth; Byrne, Susan C.; Duchen, Michael R.; Gautel, Mathias; Eskelinen, Eeva-Liisa; Fanto, Manolis; Jungbluth, Heinz (2022)
    Primary dysfunction of autophagy due to Mendelian defects affecting core components of the autophagy machinery or closely related proteins have recently emerged as an important cause of genetic disease. This novel group of human disorders may present throughout life and comprises severe early-onset neurodevelopmental and more common adult-onset neurodegenerative disorders. Early-onset (or congenital) disorders of autophagy often share a recognizable "clinical signature," including variable combinations of neurological, neuromuscular and multisystem manifestations. Structural CNS abnormalities, cerebellar involvement, spasticity and peripheral nerve pathology are prominent neurological features, indicating a specific vulnerability of certain neuronal populations to autophagic disturbance. A typically biphasic disease course of late-onset neurodegeneration occurring on the background of a neurodevelopmental disorder further supports a role of autophagy in both neuronal development and maintenance. Additionally, an associated myopathy has been characterized in several conditions. The differential diagnosis comprises a wide range of other multisystem disorders, including mitochondrial, glycogen and lysosomal storage disorders, as well as ciliopathies, glycosylation and vesicular trafficking defects. The clinical overlap between the congenital disorders of autophagy and these conditions reflects the multiple roles of the proteins and/or emerging molecular connections between the pathways implicated and suggests an exciting area for future research. Therapy development for congenital disorders of autophagy is still in its infancy but may result in the identification of molecules that target autophagy more specifically than currently available compounds. The close connection with adult-onset neurodegenerative disorders highlights the relevance of research into rare early-onset neurodevelopmental conditions for much more common, age-related human diseases.