Browsing by Author "Serrano, Geidy E."

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    A same day α-synuclein RT-QuIC seed amplification assay for synucleinopathy biospecimens
    (Springer Nature, 2025) Parveen, Sabiha; Alam, Parvez; Orrù, Christina D.; Vascellari, Sarah; Hughson, Andrew G.; Zou, Wen-Quan; Beach, Thomas G.; Serrano, Geidy E.; Goldstein, David S.; Ghetti, Bernardino; Cossu, Giovanni; Pisano, Giada; Pinna, Beatrice; Caughey, Byron; Pathology and Laboratory Medicine, School of Medicine
    Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and other synucleinopathies are characterized by the accumulation of abnormal, self-propagating aggregates of α-synuclein. RT-QuIC or seed amplification assays are currently showing unprecedented diagnostic sensitivities and specificities for synucleinopathies even in prodromal phases years in advance of the onset of Parkinsonian signs or dementia. However, commonly used α-synuclein seed amplification assays take ≥48 h to perform as applied to patients’ diagnostic biospecimens. Here, we report the development of a faster α-synuclein RT-QuIC assay that is as analytically sensitive as prior assays of this type, but can be completed in ≤12 h for brain, skin, and intestinal mucosa, with positive signals often arising in <5 h. CSF assays took a few hours longer. Our same-day α-synuclein RT-QuIC (sdRT-QuIC) assay should increase the practicality, cost-effectiveness, and throughput of measurements of pathological forms of α-synuclein for fundamental research, clinical diagnosis, and therapeutics development.
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    Adverse Social Exposome by Area Deprivation Index (ADI) and Alzheimer’s Disease and Related Dementias (ADRD) Neuropathology for a National Cohort of Brain Donors within the Neighborhoods Study
    (Wiley, 2025-01-09) Kind, Amy J. H.; Bendlin, Barbara B.; Keller, Sarah A.; Powell, W. Ryan; DeWitt, Amanda; Cheng, Yixuan; Chamberlain, Luke; Lyons Boone, Brittney; Miller, Megan J.; Vik, Stacie M.; Abner, Erin L.; Alosco, Michael L.; Apostolova, Liana G.; Bakulski, Kelly M.; Barnes, Lisa L.; Bateman, James R.; Beach, Thomas G.; Bennett, David A.; Brewer, James B.; Carrion, Carmen; Chodosh, Joshua; Craft, Suzanne; Croff, Raina; Fabio, Anthony; Tomaszewski Farias, Sarah; Goldstein, Felicia; Henderson, Victor W.; Karikari, Thomas; Kofler, Julia; Kucharska-Newton, Anna M.; Lamar, Melissa; Lanata, Serggio; Lepping, Rebecca J.; Lingler, Jennifer H.; Lockhart, Samuel N.; Mahnken, Jonathan D.; Marsh, Karyn; Meyer, Oanh L.; Miller, Bruce L.; Morris, Jill K.; Neugroschl, Judith A.; O'Connor, Maureen K.; Paulson, Henry L.; Perrin, Richard J.; Pierce, Aimee; Raji, Cyrus A.; Reiman, Eric M.; Risacher, Shannon L.; Rissman, Robert A.; Rodriguez Espinoza, Patricia; Sano, Mary; Saykin, Andrew J.; Serrano, Geidy E.; Sultzer, David L.; Whitmer, Rachel A.; Wisniewski, Thomas; Woltjer, Randall; Zhu, Carolyn W.; Neurology, School of Medicine
    Background: Adverse social exposome (indexed by high national Area Deprivation Index [ADI]) is linked to structural inequities and increased risk of clinical dementia diagnosis, yet linkage to ADRD neuropathology remains largely unknown. Early work from single site brain banks suggests a relationship, but assessment in large national cohorts is needed to increase generalizability and depth, particularly for rarer neuropathology findings. Objective: Determine the association between adverse social exposome by ADI and ADRD neuropathology for brain donors from 21 Alzheimer’s Disease Research Center (ADRC) brain banks as part of the on‐going Neighborhoods Study. Methods: All brain donors in participating sites with neuropathology data deposited at the National Alzheimer’s Coordinating Center (NACC) and identifiers for ADI linkage (N = 8,637; Figure 1) were included. Geocoded donor addresses were linked to time‐concordant national ADI percentiles for year of death, categorized into standard groupings of low (ADI 1‐19), medium (20‐49) and high (50‐100) ADI. Neuropathological findings were drawn from NACC and reflected standard assessment practices at time of donation. Logistic regression models, adjusted for sex and age at death, assessed relationships between high ADI and neuropathology findings. Results: Of the N = 8,637 brain donors (Table 1), 2,071 of 2,366 assessed (88%) had AD pathology by NIA‐AA criteria; 4,197 of 6,929 assessed (61%) had cerebral amyloid angiopathy; 2582 of 8092 assessed (32%) had Lewy body pathology; 391 of 2351 assessed (17%) had non‐AD tauopathy; and 586 of 1680 assessed (35%) had TDP‐43 pathology. 2,126(25%) were high ADI; 3,171(37%) medium ADI and 3,340(38%) low ADI with 51% female and average age at death of 81.9 years. As compared to low ADI donors, high ADI brain donors had adjusted odds = 1.35 (95% CI = 0.98‐1.86, p‐value = 0.06) for AD pathology; 1.10 (0.98–1.25, p = 0.11) for cerebral amyloid angiopathy; 1.37 (1.21–1.55, p<0.01) for Lewy body; 1.09 (0.83–1.44, p = 0.53) for non‐AD tauopathy; and 1.40 (1.08‐1.81, p = 0.01) for TDP‐43 pathology (Table 2). Conclusions: This first‐in‐field study provides evidence that the adverse social exposome (high ADI) is strongly associated with an increased risk of Lewy body, an increased risk of TDP‐43, and a trend towards increased AD pathology in a national cohort of brain donors.
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    Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub-haplotypes
    (medRxiv, 2024-02-28) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Si, Ya-Qin; Tucci, Albert; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Alex, Rajput; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivianna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw R.; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; PSP genetics study group; Dickson, Dennis W.; Höglinger, Günter U.; Tzeng, Jung-Ying; Geschwind, Daniel H.; Schellenberg, Gerard D.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
    Importance: The chromosome 17q21.31 region, containing a 900 Kb inversion that defines H1 and H2 haplotypes, represents the strongest genetic risk locus in progressive supranuclear palsy (PSP). In addition to H1 and H2, various structural forms of 17q21.31, characterized by the copy number of α, β, and γ duplications, have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study. Objective: To assess the association of different structural forms of 17q.21.31, defined by the copy numbers of α, β, and γ duplications, with the risk of PSP and MAPT sub-haplotypes. Design setting and participants: Utilizing whole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects, a case-control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP. All study subjects were selected from the Alzheimer's Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Data were analyzed between March 2022 and November 2023. Main outcomes and measures: The main outcomes were the risk (odds ratios [ORs]) for PSP with 95% CIs. Risks for PSP were evaluated by logistic regression models. Results: The copy numbers of α and β were associated with the risk of PSP only due to their correlation with H1 and H2, while the copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04-1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For the H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10-1.33, P = 5.47 × 10-5) for H1β1γ1 to 1.29 (95%CI 1.16-1.43, P = 1.35 × 10-6) for H1β1γ2, 1.45 (95%CI 1.27-1.65, P = 3.94 × 10-8) for H1β1γ3, and 1.57 (95%CI 1.10-2.26, P = 1.35 × 10-2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub-haplotype associated with increased risk of PSP. The proportion of MAPT sub-haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increased from 34% in H1β1γ1 to 77% in H1β1γ4. Conclusions and relevance: This study revealed that the copy number of γ was associated with the risk of PSP independently from H1 and H2. The H1 haplotype with more γ duplications showed a higher odds ratio for PSP and were associated with MAPT sub-haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure at 17q21.31 affect the risk of PSP.
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    Biomarker-Based Approach to α-Synucleinopathies: Lessons from Neuropathology
    (Wiley, 2024) Kovacs, Gabor G.; Grinberg, Lea T.; Halliday, Glenda; Alafuzoff, Irina; Dugger, Brittany N.; Murayama, Shigeo; Forrest, Shelley L.; Martinez-Valbuena, Ivan; Tanaka, Hidetomo; Kon, Tomoya; Yoshida, Koji; Jaunmuktane, Zane; Spina, Salvatore; Nelson, Peter T.; Gentleman, Steve; Alegre-Abarrategui, Javier; Serrano, Geidy E.; Paes, Vitor Ribeiro; Takao, Masaki; Wakabayashi, Koichi; Uchihara, Toshiki; Yoshida, Mari; Saito, Yuko; Kofler, Julia; Diehl Rodriguez, Roberta; Gelpi, Ellen; Attems, Johannes; Crary, John F.; Seeley, William W.; Duda, John E.; Keene, C. Dirk; Woulfe, John; Munoz, David; Smith, Colin; Lee, Edward B.; Neumann, Manuela; White, Charles L., III; McKee, Ann C.; Thal, Dietmar R.; Jellinger, Kurt; Ghetti, Bernardino; Mackenzie, Ian R. A.; Dickson, Dennis W.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of Medicine
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    Cellular localization of p-tau217 in brain and its association with p-tau217 plasma levels
    (BMC, 2022) Wennström, Malin; Janelidze, Shorena; Nilsson, K. Peter R.; The Netherlands Brain Bank; Serrano, Geidy E.; Beach, Thomas G.; Dage, Jeffrey L.; Hansson, Oskar; Neurology, School of Medicine
    Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer's disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load.
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    Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes
    (Oxford University Press, 2025) Sepulveda-Falla, Diego; Villegas Lanau, Carlos Andrés; White, Charles, III; Serrano, Geidy E.; Acosta-Uribe, Juliana; Mejía-Cupajita, Barbara; Villalba-Moreno, Nelson David; Lu, Pinzhang; Glatzel, Markus; Kofler, Julia K.; Ghetti, Bernardino; Frosch, Matthew P.; Restrepo, Francisco Lopera; Kosik, Kenneth S.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of Medicine
    Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.
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    Comorbidities in Early-Onset Sporadic versus Presenilin-1 Mutation-Associated Alzheimer’s Disease Dementia: Evidence for Dependency on Alzheimer’s Disease Neuropathological Changes
    (medRxiv, 2023-08-16) Sepulveda-Falla, Diego; Lanau, Carlos Andrés Villegas; White, Charles, III; Serrano, Geidy E.; Acosta-Uribe, Juliana; Mejía-Cupajita, Barbara; Villalba-Moreno, Nelson David; Lu, Pinzhang; Glatzel, Markus; Kofler, Julia K.; Ghetti, Bernardino; Frosch, Matthew P.; Restrepo, Francisco Lopera; Kosik, Kenneth S.; Beach, Thomas G.; Pathology and Laboratory Medicine, School of Medicine
    Autopsy studies have demonstrated that comorbid neurodegenerative and cerebrovascular disease occur in the great majority of subjects with Alzheimer disease dementia (ADD), and are likely to additively alter the rate of decline or severity of cognitive impairment. The most important of these are Lewy body disease (LBD), TDP-43 proteinopathy and cerebrovascular disease, including white matter rarefaction (WMR) and cerebral infarcts. Comorbidities may interfere with ADD therapeutic trials evaluation of ADD clinical trials as they may not respond to AD-specific molecular therapeutics. It is possible, however, that at least some comorbidities may be, to some degree, secondary consequences of AD pathology, and if this were true then effective AD-specific therapeutics might also reduce the extent or severity of comorbid pathology. Comorbidities in ADD caused by autosomal dominant mutations such as those in the presenilin-1 (PSEN1) gene may provide an advantageous perspective on their pathogenesis, and deserve attention because these subjects are increasingly being entered into clinical trials. As ADD associated with PSEN1 mutations has a presumed single-cause etiology, and the average age at death is under 60, any comorbidities in this setting may be considered as at least partially secondary to the causative AD mechanisms rather than aging, and thus indicate whether effective ADD therapeutics may also be effective for comorbidities. In this study, we sought to compare the rates and types of ADD comorbidities between subjects with early-onset sporadic ADD (EOSADD; subjects dying under age 60) versus ADD associated with different types of PSEN1 mutations, the most common cause of early-onset autosomal dominant ADD. In particular, we were able to ascertain, for the first time, the prevalences of a fairly complete set of ADD comorbidities in United States (US) PSEN1 cases as well as the Colombian E280A PSEN1 kindred. Data for EOSADD and US PSEN1 subjects (with multiple different mutation types) was obtained from the National Alzheimer Coordinating Center (NACC). Colombian cases all had the E280A mutation and had a set of neuropathological observations classified, like the US cases according to the NACC NP10 definitions. Confirmatory of earlier reports, NACC-defined Alzheimer Disease Neuropathological Changes (ADNC) were consistently very severe in early-onset cases, whether sporadic or in PSEN1 cases, but were slightly less severe in EOSADD. Amyloid angiopathy was the only AD-associated pathology type with widely-differing severity scores between the 3 groups, with median scores of 3, 2 and 1 in the PSEN1 Colombia, PSEN1 US and EOSADD cases, respectively. Apoliprotein E genotype did not show significant proportional group differences for the possession of an E-4 or E-2 allele. Of ADD comorbidities, LBD was most common, being present in more than half of all cases in all 3 groups. For TDP-43 co-pathology, the Colombian PSEN1 group was the most affected, at about 27%, vs 16% and 11% for the US PSEN1 and sporadic US cases, respectively. Notably, hippocampal sclerosis and non-AD tau pathological conditions were not present in any of the US or Colombian PSEN1 cases, and was seen in only 3% of the EOSADD cases. Significant large-vessel atherosclerosis was present in a much larger percentage of Colombian PSEN1 cases, at almost 20% as compared to 0% and 3% of the US PSEN1 and EOSADD cases, respectively. Small-vessel disease, or arteriolosclerosis, was much more common than large vessel disease, being present in all groups between 18% and 37%. Gross and microscopic infarcts, however, as well as gross or microscopic hemorrhages, were generally absent or present at very low percentages in all groups. White matter rarefaction (WMR) was remarkably common, at almost 60%, in the US PSEN1 group, as compared to about 18% in the EOSADD cases, a significant difference. White matter rarefaction was not assessed in the Colombian PSEN1 cases. The results presented here, as well as other evidence, indicates that LBD, TDP-43 pathology and WMR, as common comorbidities with autosomal dominant and early-onset sporadic ADD, should be considered when planning clinical trials with such subjects as they may increase variability in response rates. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.
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    Correction: Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy
    (Springer Nature, 2024-10-14) Wang, Hui; Chang, Timothy S.; Dombroski, Beth A.; Cheng, Po-Liang; Patil, Vishakha; Valiente-Banuet, Leopoldo; Farrell, Kurt; Mclean, Catriona; Molina-Porcel, Laura; Rajput, Alex; De Deyn, Peter Paul; Le Bastard, Nathalie; Gearing, Marla; Donker Kaat, Laura; Van Swieten, John C.; Dopper, Elise; Ghetti, Bernardino F.; Newell, Kathy L.; Troakes, Claire; de Yébenes, Justo G.; Rábano-Gutierrez, Alberto; Meller, Tina; Oertel, Wolfgang H.; Respondek, Gesine; Stamelou, Maria; Arzberger, Thomas; Roeber, Sigrun; Müller, Ulrich; Hopfner, Franziska; Pastor, Pau; Brice, Alexis; Durr, Alexandra; Le Ber, Isabelle; Beach, Thomas G.; Serrano, Geidy E.; Hazrati, Lili-Naz; Litvan, Irene; Rademakers, Rosa; Ross, Owen A.; Galasko, Douglas; Boxer, Adam L.; Miller, Bruce L.; Seeley, Willian W.; Van Deerlin, Vivanna M.; Lee, Edward B.; White, Charles L., III; Morris, Huw; de Silva, Rohan; Crary, John F.; Goate, Alison M.; Friedman, Jeffrey S.; Leung, Yuk Yee; Coppola, Giovanni; Naj, Adam C.; Wang, Li-San; P. S. P. genetics study group; Dalgard, Clifton; Dickson, Dennis W.; Höglinger, Günter U.; Schellenberg, Gerard D.; Geschwind, Daniel H.; Lee, Wan-Ping; Pathology and Laboratory Medicine, School of Medicine
    Correction : Mol Neurodegeneration 19, 61 (2024) https://doi.org/10.1186/s13024-024-00747-3 The original article [1] erroneously gives a wrong affiliation for Ulrich Müller. His correct affiliation is Institute of Human Genetics, Justus-Liebig University Giessen, 35392 Giessen, Germany.
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    Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease
    (medRxiv, 2023-04-24) Valentino, Rebecca R.; Scotton, William J.; Roemer, Shanu F.; Lashley, Tammaryn; Heckman, Michael G.; Shoai, Maryam; Martinez-Carrasco, Alejandro; Tamvaka, Nicole; Walton, Ronald L.; Baker, Matthew C.; Macpherson, Hannah L.; Real, Raquel; Soto-Beasley, Alexandra I.; Mok, Kin; Revesz, Tamas; Warner, Thomas T.; Jaunmuktane, Zane; Boeve, Bradley F.; Christopher, Elizabeth A.; DeTure, Michael; Duara, Ranjan; Graff-Radford, Neill R.; Josephs, Keith A.; Knopman, David S.; Koga, Shunsuke; Murray, Melissa E.; Lyons, Kelly E.; Pahwa, Rajesh; Parisi, Joseph E.; Petersen, Ronald C.; Whitwell, Jennifer; Grinberg, Lea T.; Miller, Bruce; Schlereth, Athena; Seeley, William W.; Spina, Salvatore; Grossman, Murray; Irwin, David J.; Lee, Edward B.; Suh, EunRan; Trojanowski, John Q.; Van Deerlin, Vivianna M.; Wolk, David A.; Connors, Theresa R.; Dooley, Patrick M.; Frosch, Matthew P.; Oakley, Derek H.; Aldecoa, Iban; Balasa, Mircea; Gelpi, Ellen; Borrego-Écija, Sergi; de Eugenio Huélamo, Rosa Maria; Gascon-Bayarri, Jordi; Sánchez-Valle, Raquel; Sanz-Cartagena, Pilar; Piñol-Ripoll, Gerard; Molina-Porcel, Laura; Bigio, Eileen H.; Flanagan, Margaret E.; Gefen, Tamar; Rogalski, Emily J.; Weintraub, Sandra; Redding-Ochoa, Javier; Chang, Koping; Troncoso, Juan C.; Prokop, Stefan; Newell, Kathy L.; Ghetti, Bernardino; Jones, Matthew; Richardson, Anna; Robinson, Andrew C.; Roncaroli, Federico; Snowden, Julie; Allinson, Kieren; Green, Oliver; Rowe, James B.; Singh, Poonam; Beach, Thomas G.; Serrano, Geidy E.; Flowers, Xena E.; Goldman, James E.; Heaps, Allison C.; Leskinen, Sandra P.; Teich, Andrew F.; Black, Sandra E.; Keith, Julia L.; Masellis, Mario; Bodi, Istvan; King, Andrew; Sarraj, Safa-Al; Troakes, Claire; Halliday, Glenda M.; Hodges, John R.; Kril, Jillian J.; Kwok, John B.; Piguet, Olivier; Gearing, Marla; Arzberger, Thomas; Roeber, Sigrun; Attems, Johannes; Morris, Christopher M.; Thomas, Alan J.; Evers, Bret M.; White, Charles L.; Mechawar, Naguib; Sieben, Anne A.; Cras, Patrick P.; De Vil, Bart B.; De Deyn, Peter Paul P. P.; Duyckaerts, Charles; Le Ber, Isabelle; Seihean, Danielle; Turbant-Leclere, Sabrina; MacKenzie, Ian R.; McLean, Catriona; Cykowski, Matthew D.; Ervin, John F.; Wang, Shih-Hsiu J.; Graff, Caroline; Nennesmo, Inger; Nagra, Rashed M.; Riehl, James; Kovacs, Gabor G.; Giaccone, Giorgio; Nacmias, Benedetta; Neumann, Manuela; Ang, Lee-Cyn; Finger, Elizabeth C.; Blauwendraat, Cornelis; Nalls, Mike A.; Singleton, Andrew B.; Vitale, Dan; Cunha, Cristina; Carvalho, Agostinho; Wszolek, Zbigniew K.; Morris, Huw R.; Rademakers, Rosa; Hardy, John A.; Dickson, Dennis W.; Rohrer, Jonathan D.; Ross, Owen A.; Pathology and Laboratory Medicine, School of Medicine
    Background: Pick's disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by argyrophilic inclusion Pick bodies and ballooned neurons in the frontal and temporal brain lobes. PiD is characterised by the presence of Pick bodies which are formed from aggregated, hyperphosphorylated, 3-repeat tau proteins, encoded by the MAPT gene. The MAPT H2 haplotype has consistently been associated with a decreased disease risk of the 4-repeat tauopathies of progressive supranuclear palsy and corticobasal degeneration, however its role in susceptibility to PiD is unclear. The primary aim of this study was to evaluate the association between MAPT H2 and risk of PiD. Methods: We established the Pick's disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 39 sites worldwide. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic Jacksonville, FL (N=881) or Rochester, MN (N=431). For the primary analysis, subjects were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes (rs1467967, rs242557, rs3785883, rs2471738, rs8070723, and rs7521). Findings: Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, 95% CI: 1.12-1.64 P=0.002). In secondary analysis involving H1 subhaplotypes, a protective association with PiD was observed for the H1f haplotype (0.0% vs. 1.2%, P=0.049), with a similar trend noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). The 4-repeat tauopathy risk haplotype MAPT H1c was not associated with PiD susceptibility (OR: 0.93, 95% CI: 0.70-1.25, P=0.65). Interpretation: The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to its protective role in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.
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    Differential methylation analysis in neuropathologically confirmed dementia with Lewy bodies
    (Springer Nature, 2024-01-05) Reho, Paolo; Saez-Atienzar, Sara; Ruffo, Paola; Solaiman, Sultana; Shah, Zalak; Chia, Ruth; Kaivola, Karri; Traynor, Bryan J.; Tilley, Bension S.; Gentleman, Steve M.; Hodges, Angela K.; Aarsland, Dag; Monuki, Edwin S.; Newell, Kathy L.; Woltjer, Randy; Albert, Marilyn S.; Dawson, Ted M.; Rosenthal, Liana S.; Troncoso, Juan C.; Pletnikova, Olga; Serrano, Geidy E.; Beach, Thomas G.; Easwaran, Hariharan P.; Scholz, Sonja W.; Pathology and Laboratory Medicine, School of Medicine
    Dementia with Lewy bodies (DLB) is a common form of dementia in the elderly population. We performed genome-wide DNA methylation mapping of cerebellar tissue from pathologically confirmed DLB cases and controls to study the epigenetic profile of this understudied disease. After quality control filtering, 728,197 CpG-sites in 278 cases and 172 controls were available for the analysis. We undertook an epigenome-wide association study, which found a differential methylation signature in DLB cases. Our analysis identified seven differentially methylated probes and three regions associated with DLB. The most significant CpGs were located in ARSB (cg16086807), LINC00173 (cg18800161), and MGRN1 (cg16250093). Functional enrichment evaluations found widespread epigenetic dysregulation in genes associated with neuron-to-neuron synapse, postsynaptic specialization, postsynaptic density, and CTCF-mediated synaptic plasticity. In conclusion, our study highlights the potential importance of epigenetic alterations in the pathogenesis of DLB and provides insights into the modified genes, regions and pathways that may guide therapeutic developments.