Article
Clinical Neurology
Elena Fontana, Matilde Bongianni, Alberto Benussi, Erika Bronzato, Carlo Scialo, Luca Sacchetto, Annachiara Cagnin, Santina Castriciano, Emanuele Buratti, Fabrizio Gardoni, Maria Italia, Alberto Schreiber, Chiara Ferracin, Michele Fiorini, Kathy L. Newell, Laura Cracco, Holly J. Garringer, Maria Paola Cecchini, Magdalini Polymenidou, Alessandro Padovani, Salvatore Monaco, Giuseppe Legname, Bernardino Ghetti, Barbara Borroni, Gianluigi Zanusso
Summary: TDP-43 aggregates were detected in the olfactory mucosa, suggesting that TDP43-SAA may be useful for identifying and monitoring FTLD-TDP in living patients.
ALZHEIMERS & DEMENTIA
(2023)
Article
Neurosciences
Alba Cervantes Gonzalez, David J. Irwin, Daniel Alcolea, Corey T. McMillan, Alice Chen-Plotkin, David Wolk, Sonia Sirisi, Oriol Dols-Icardo, Marta Querol-Vilaseca, Ignacio Illan-Gala, Miguel Angel Santos-Santos, Juan Fortea, Edward B. Lee, John Q. Trojanowski, Murray Grossman, Alberto Lleo, Olivia Belbin
Summary: The study found an association between synaptic proteins and pathological burden and cognitive performance in frontotemporal lobar degeneration (FTLD) patients. These synaptic panels have the potential to differentiate FTLD neuropathologic subtypes and serve as surrogate markers for cognitive performance in future clinical trials.
MOLECULAR NEURODEGENERATION
(2022)
Article
Neurosciences
Senthil T. Kumar, Sergey Nazarov, Silvia Porta, Niran Maharjan, Urszula Cendrowska, Malek Kabani, Francesco Finamore, Yan Xu, Virginia M. -Y. Lee, Hilal A. Lashuel
Summary: Reconstitution of TDP-43 filaments with sequence and morphological features similar to those found in the brain reveals a new mechanism for the formation and propagation of pathology in amyotrophic lateral sclerosis and other neurodegenerative diseases.
NATURE NEUROSCIENCE
(2023)
Article
Clinical Neurology
Takashi Kurashige, Hiroyuki Morino, Tomomi Murao, Yuishin Izumi, Tomohito Sugiura, Kazuya Kuraoka, Hideshi Kawakami, Tsuyoshi Torii, Hirofumi Maruyama
Summary: The study aims to identify and characterize the histopathology of peripheral axons in the skeletal muscle of patients with ALS. The results suggest that axonal pTDP-43 accumulations may be characteristic for patients with ALS, and it could be a potential novel diagnostic biomarker for ALS.
Review
Biochemistry & Molecular Biology
Clement Barbereau, Nicolas Cubedo, Tangui Maurice, Mireille Rossel
Summary: Tauopathies encompass a diverse range of neurodegenerative diseases, with Alzheimer's disease being the most prominent one. Accumulation of abnormal forms of Tau protein in neural cells leads to its aggregation and neurofibrillary tangles, contributing to cognitive deficits and locomotor problems. Zebrafish transgenic models have been instrumental in studying Tau protein interactions and exploring neuroprotective approaches against Tau-related pathologies.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
Lauren M. Forgrave, Kyung-Mee Moon, Jordan E. Hamden, Yun Li, Phoebe Lu, Leonard J. Foster, Ian R. A. Mackenzie, Mari L. DeMarco
Summary: Biomarkers of TDP-43 pathology are needed to differentiate FTLD-TDP from related disorders. Using high-resolution mass spectrometry, we identified truncated TDP-43 as a potential biomarker with high diagnostic accuracy for FTLD-TDP.
ALZHEIMERS & DEMENTIA
(2023)
Article
Neurosciences
Manling Xie, Yong U. Liu, Shunyi Zhao, Lingxin Zhang, Dale B. Bosco, Yuan-Ping Pang, Jun Zhong, Udit Sheth, Yuka A. Martens, Na Zhao, Chia-Chen Liu, Yongxian Zhuang, Liewei Wang, Dennis W. Dickson, Mark P. Mattson, Guojun Bu, Long-Jun Wu
Summary: The study reveals that TREM2 plays a crucial role in TDP-43-related neurodegeneration, with TREM2 deficiency exacerbating neuronal damage and motor impairments. Mass cytometry analysis and surface plasmon resonance analysis demonstrate the interaction between TDP-43 and TREM2.
NATURE NEUROSCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Shailendra Dhakal, Alicia S. Robang, Nemil Bhatt, Nicha Puangmalai, Leiana Fung, Rakez Kayed, Anant K. Paravastu, Vijayaraghavan Rangachari
Summary: This research highlights the interaction between different amyloid proteins in forming heterotypic amyloid aggregates, providing a molecular basis for overlapping neurodegenerative diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Geriatrics & Gerontology
Enrico Premi, Maria Cotelli, Elena Gobbi, Ilaria Pagnoni, Giuliano Binetti, Yasmine Gadola, Ilenia Libri, Irene Mattioli, Marta Pengo, Armin Iraji, Vince D. Calhoun, Antonella Alberici, Barbara Borroni, Rosa Manenti
Summary: This study investigates the neuroanatomical correlates of language deficits in avPPA using verbal fluency tasks, AAT naming subtest, and SAND scores as proxies of brain structural imaging abnormalities.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Review
Biochemistry & Molecular Biology
Merel O. Mol, Suzanne S. M. Miedema, John C. van Swieten, Jeroen G. J. van Rooij, Elise G. P. Dopper
Summary: FTLD is a neurodegenerative disorder with major impact on patients and their families, mainly characterized by TDP-43 proteinopathy. The exact mechanisms driving FTLD-TDP remain largely unknown, but proteomic approaches hold promise to elucidate pathogenic molecular and cellular alterations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
Cyril Pottier, Ligia Mateiu, Matthew C. Baker, Mariely DeJesus-Hernandez, Cristina Teixeira Vicente, NiCole A. Finch, Shulan Tian, Marka van Blitterswijk, Melissa E. Murray, Yingxue Ren, Leonard Petrucelli, Bjorn Oskarsson, Joanna M. Biernacka, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, Keith A. Josephs, Yan W. Asmann, Dennis W. Dickson, Rosa Rademakers
Summary: By comparing gene expression, the researchers found that patients with GRN mutations and those with unknown mutations have similar transcriptional profiles, involving several potentially druggable pathways. These findings reveal novel disease mechanisms in FTLD and strongly suggest that GRN mutations extend beyond GRN and contribute to genetically unexplained forms of FTLD.
Article
Neurosciences
Rachel H. Tan, Heather McCann, Claire E. Shepherd, Monica Pinkerton, Srestha Mazumder, Emma M. Devenney, Gabrielle L. Adler, Dominic B. Rowe, Jillian Kril, Glenda M. Halliday, Matthew C. Kiernan
Summary: Despite the presence of significant cortical pTDP-43 inclusions of heterogeneous morphologies in patients diagnosed with ALS, pathological subclassification is routinely performed in the minority of patients with concomitant FTD. In this study, three distinct ALS-TDP subtypes were identified based on the presence, morphology, and composition of pTDP-43 pathology. These subtypes show different levels of pTDP-43 burden and are associated with different neuropathological changes and cognitive scores.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2023)
Article
Neurosciences
Sarah Pickles, Tania F. Gendron, Yuka Koike, Mei Yue, Yuping Song, Jennifer M. Kachergus, J. Shi, Michael DeTure, E. Aubrey Thompson, Bjorn Oskarsson, Neill R. Graff-Radford, Bradley F. Boeve, Ronald C. Petersen, Zbigniew K. Wszolek, Keith A. Josephs, Dennis W. Dickson, Leonard Petrucelli, Casey N. Cook, Mercedes Prudencio
Summary: This study found that the cerebellum plays an important role in FTLD-TDP, with decreased levels of TDP-43 protein and increased levels of truncated STMN2 transcripts, indicating TDP-43 dysfunction. Lower cerebellar TDP-43 was also associated with younger age at disease onset. These findings suggest that further investigation into the role of the cerebellum in FTLD-TDP is warranted.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Multidisciplinary Sciences
Yi Xiao Jiang, Qin Cao, Michael R. Sawaya, Romany Abskharon, Peng Ge, Michael DeTure, Dennis W. Dickson, Janine Y. Fu, Rachel R. Ogorzalek Loo, Joseph A. Loo, David S. Eisenberg
Summary: This study found that amyloid fibrils in FTLD-TDP patients are formed by TMEM106B protein rather than TDP-43 protein. In addition, abundant non-fibrillar aggregated TDP-43 protein was observed.
Review
Clinical Neurology
Arenn F. Carlos, Keith A. Josephs
Summary: This paper reviews how FTLD-TDP was established and defined clinically and neuropathologically throughout the past century.
JOURNAL OF NEUROLOGY
(2022)
Article
Clinical Neurology
Janina Krell-Roesch, Martin Rakusa, Jeremy A. Syrjanen, Argonde C. van Harten, Val J. Lowe, Clifford R. Jack, Walter K. Kremers, David S. Knopman, Gorazd B. Stokin, Ronald C. Petersen, Maria Vassilaki, Yonas E. Geda
Summary: This study examined the association between CSF biomarkers of Alzheimer's disease and neuropsychiatric symptoms in older non-demented adults. The results showed that lower CSF Aβ42 and higher t-tau/Aβ42 and p-tau/Aβ42 ratios were associated with depression, anxiety, and other NPS.
ALZHEIMERS & DEMENTIA
(2023)
Article
Clinical Neurology
Neha Atulkumar Singh, Nirubol Tosakulwong, Jonathan Graff-Radford, Mary M. Machulda, Nha Trang Thu Pham, Irene Sintini, Stephen D. Weigand, Christopher G. Schwarz, Matthew L. Senjem, Minerva M. Carrasquillo, Nilufer Ertekin-Taner, Clifford R. Jack, Val J. Lowe, Keith A. Josephs, Jennifer L. Whitwell
Summary: APOE epsilon 4 is an important genetic risk factor for typical Alzheimer's disease (AD), but its influence in atypical presentations of AD is not well-known. This study found that APOE epsilon 4 carriers had smaller hippocampal and amygdala volumes and greater tau deposition, while non-carriers showed faster rates of atrophy and tau accumulation in certain brain regions.
ALZHEIMERS & DEMENTIA
(2023)
Article
Oncology
Firat Kara, Christine M. Lohse, Anna M. Castillo, Nirubol Tosakulwong, Timothy G. Lesnick, Clifford R. Jack, Ronald C. Petersen, Janet E. Olson, Fergus J. Couch, Kathryn J. Ruddy, Kejal Kantarci, Michelle M. Mielke
Summary: This study aimed to investigate whether the use of selective estrogen receptor modifiers (SERMs), including tamoxifen and raloxifene, was associated with cognitive performance and markers of neurodegeneration associated with Alzheimer's disease. The results showed no significant associations between the use of SERMs and cognition or MCI in both breast cancer patients and women without a history of cancer.
Article
Clinical Neurology
Nicholas B. B. Martin, Shunsuke Koga, Brian S. S. Appleby, Hiroaki Sekiya, Dennis W. Dickson
Summary: Two cases of patients who were misdiagnosed with multiple system atrophy (MSA) actually had Creutzfeldt-Jakob disease (CJD), as confirmed by neuropathological findings. This suggests that when the disease progresses rapidly or the clinical course is atypical, even if clinical features suggest MSA, the possibility of CJD should also be considered.
MOVEMENT DISORDERS CLINICAL PRACTICE
(2023)
Article
Clinical Neurology
Clifford R. Jack Jr, Heather J. Wiste, Alicia Algeciras-Schimnich, Dan J. Figdore, Christopher G. Schwarz, Val J. Lowe, Vijay K. Ramanan, Prashanthi Vemuri, Michelle M. Mielke, David S. Knopman, Jonathan Graff-Radford, Bradley F. Boeve, Kejal Kantarci, Petrice M. Cogswell, Matthew L. Senjem, Jeffrey L. Gunter, Terry M. Therneau, Ronald C. Petersen
Summary: Staging the severity of Alzheimer's disease pathology is important for therapeutic trials and clinical prognosis. Biomarkers such as amyloid and tau PET can be used for disease staging, but plasma biomarkers would be more practical.
Article
Clinical Neurology
Vijay K. Ramanan, Robel K. Gebre, Jonathan Graff-Radford, Ekaterina Hofrenning, Alicia Algeciras-Schimnich, Daniel J. Figdore, Val J. Lowe, Michelle M. Mielke, David S. Knopman, Owen A. Ross, Clifford R. Jack Jr, Ronald C. Petersen, Prashanthi Vemuri
Summary: Ramanan et al. found that integrating genetic risk scores improves the diagnostic value of plasma biomarkers for Alzheimer's disease, especially in predicting amyloid PET positivity. However, more advances are needed before these biomarkers can be widely used. By analyzing a large sample, they discovered that the AD-GRS is independently associated with amyloid PET levels and significantly enhances the classification accuracy of amyloid PET positivity when combined with high plasma p-tau(181). Machine learning methods that incorporate plasma biomarkers, demographics, and the AD-GRS show high accuracy in predicting amyloid PET levels.
Article
Clinical Neurology
Diego Z. Carvalho, Stuart J. McCarter, Erik K. St Louis, Scott A. Przybelski, Kohl Johnson L. Sparrman, Virend K. Somers, Bradley F. Boeve, Ronald C. Petersen, Clifford R. Jack Jr, Jonathan Graff-Radford, Prashanthi Vemuri
Summary: This study aimed to investigate the association between polysomnographic (PSG) sleep parameters and neuroimaging biomarkers of cerebrovascular disease (CVD) in older adults with obstructive sleep apnea (OSA). The results showed that reduced slow-wave sleep and severe OSA were associated with increased burden of white matter abnormalities in older adults, which may contribute to a higher risk of cognitive impairment, dementia, and stroke.
Article
Multidisciplinary Sciences
Petrice M. Cogswell, Emily S. Lundt, Terry M. Therneau, Carly T. Mester, Heather J. Wiste, Jonathan Graff-Radford, Christopher G. Schwarz, Matthew L. Senjem, Jeffrey L. Gunter, Robert I. Reid, Scott A. Przybelski, David S. Knopman, Prashanthi Vemuri, Ronald C. Petersen, Clifford R. Jack
Summary: The potential connection between cerebrovascular disease and Alzheimer's disease has been controversial. This study finds a weak temporal relationship between the progression of Alzheimer's disease biomarkers and cerebrovascular disease biomarkers.
NATURE COMMUNICATIONS
(2023)
Article
Clinical Neurology
Nick Corriveau-Lecavalier, Jeffrey L. Gunter, Michael Kamykowski, Ellen Dicks, Hugo Botha, Walter K. Kremers, Jonathan Graff-Radford, Daniela A. Wiepert, Christopher G. Schwarz, Essa Yacoub, David S. Knopman, Bradley F. Boeve, Kamil Ugurbil, Ronald C. Petersen, Clifford R. Jack, Melissa J. Terpstra, David T. Jones
Summary: From a complex systems perspective, clinical syndromes emerging from neurodegenerative diseases are thought to result from multiscale interactions between aggregates of misfolded proteins and the disequilibrium of large-scale networks coordinating functional operations underpinning cognitive phenomena. Age-related disruption of the default mode network is accelerated by amyloid deposition in all syndromic presentations of Alzheimer's disease, while syndromic variability may reflect selective neurodegeneration of modular networks supporting specific cognitive abilities. This study investigates the use of a biomarker of default mode network dysfunction, the network failure quotient, to assess Alzheimer's disease in a normative cohort and differentiate between different phenotypes of the disease. The study provides important insights into the shared pathophysiological mechanisms and distinct neurodegenerative processes involved in Alzheimer's disease.
BRAIN COMMUNICATIONS
(2023)
Article
Neurosciences
Nicole S. McKay, Brian A. Gordon, Russ C. Hornbeck, Aylin Dincer, Shaney Flores, Sarah J. Keefe, Nelly Joseph-Mathurin, Clifford R. Jack, Robert Koeppe, Peter R. Millar, Beau M. Ances, Charles D. Chen, Alisha Daniels, Diana A. Hobbs, Kelley Jackson, Deborah Koudelis, Parinaz Massoumzadeh, Austin McCullough, Michael L. Nickels, Farzaneh Rahmani, Laura Swisher, Qing Wang, Ricardo F. Allegri, Sarah B. Berman, Adam M. Brickman, William S. Brooks, David M. Cash, Jasmeer P. Chhatwal, Gregory S. Day, Martin R. Farlow, Christian la Fougere, Nick C. Fox, Michael Fulham, Bernardino Ghetti, Neill Graff-Radford, Takeshi Ikeuchi, William Klunk, Jae-Hong Lee, Johannes Levin, Ralph Martins, Colin L. Masters, Jonathan McConathy, Hiroshi Mori, James Noble, Gerald Reischl, Christopher Rowe, Stephen Salloway, Raquel Sanchez-Valle, Peter R. Schofield, Hiroyuki Shimada, Mikio Shoji, Yi Su, Kazushi Suzuki, Jonathan Voeglein, Igor Yakushev, Carlos Cruchaga, Jason Hassenstab, Celeste Karch, Eric McDade, Richard J. Perrin, Chengjie Xiong, John C. Morris, Randall J. Bateman, Tammie L. S. Benzinger
Summary: The Dominantly Inherited Alzheimer Network (DIAN) is an international collaboration that studies autosomal dominant Alzheimer disease (ADAD). ADAD arises from mutations in three genes. Non-carrier siblings from ADAD families can be recruited for case-control studies. The predictable age of onset in ADAD allows for mapping candidate AD biomarkers during the preclinical phase. This study provides valuable data for understanding early disease stages of both ADAD and sporadic AD, as well as for research in healthy aging.
NATURE NEUROSCIENCE
(2023)
Article
Neurosciences
Christopher G. Schwarz, Walter K. Kremers, Arvin Arani, Marios Savvides, Robert I. Reid, Jeffrey L. Gunter, Matthew L. Senjem, Petrice M. Cogswell, Prashanthi Vemuri, Kejal Kantarci, David S. Knopman, Ronald C. Petersen, Clifford R. Jack
Summary: It is now known that research brain MRI, CT, and PET images may be re-identified using face recognition, but applying face-deidentification software can reduce this risk. The re-identification potential and effects of de-facing are unknown for certain research MRI sequences. In this study, the re-identification rates were examined for different MRI sequences, and it was found that high-quality de-facing software can greatly reduce the risk of re-identification for identifiable MRI sequences.
Article
Clinical Neurology
Hiroaki Sekiya, Shunsuke Koga, Aya Murakami, Miki Kawazoe, Minji Kim, Nicholas B. Martin, Ryan J. Uitti, William P. Cheshire, Zbigniew K. Wszolek, Dennis W. Dickson
Summary: The study compared the diagnostic accuracy of the MDS criteria and second consensus criteria for MSA, finding that the MDS criteria had higher specificity for clinically established and probable MSA, while the second consensus criteria had higher sensitivity for probable and possible MSA.
Article
Clinical Neurology
Srishti Shrestha, Xiaoqian Zhu, Kevin J. Sullivan, Chad Blackshear, Jennifer A. Deal, A. Richey Sharrett, Vidyulata Kamath, Andrea L. C. Schneider, Clifford R. Jack, Juebin Huang, Priya Palta, Robert I. Reid, David S. Knopman, Rebecca F. Gottesman, Honglei Chen, B. Gwen Windham, Michael E. Griswold, Jr Thomas H. Mosley
Summary: Research shows that neuronal microstructural integrity in multiple brain regions, particularly the medial temporal lobe (MTL), is associated with odor identification ability. The associations between microstructural integrity and olfaction are stronger in individuals with mild cognitive impairment (MCI) compared to those with normal cognition, suggesting different effects of dementia pathogenesis.
Article
Multidisciplinary Sciences
Junhao Li, Manoj K. Jaiswal, Jo-Fan Chien, Alexey Kozlenkov, Jinyoung Jung, Ping Zhou, Mahammad Gardashli, Luc J. Pregent, Erica Engelberg-Cook, Dennis W. Dickson, Veronique V. Belzil, Eran A. Mukamel, Stella Dracheva
Summary: The repeat expansion in the C9orf72 gene is a common genetic cause of ALS and FTD. The study found pervasive alterations in gene expression and chromatin accessibility in neurons and astrocytes of C9-ALS patients, as well as gene expression changes in glial cells of C9-FTD patients. These findings indicate unique molecular disruptions in different cell types, brain regions, and diseases.
NATURE COMMUNICATIONS
(2023)
Article
Genetics & Heredity
Aimee R. Herdt, Hui Peng, Dennis W. Dickson, Todd E. Golde, Elizabeth A. Eckman, Chris W. Lee
Summary: Krabbe disease is a neurologic disorder characterized by the accumulation of psychosine in the CNS. In a mouse model, treatment with AAV1-GALC, a viral vector expressing GALC, significantly improved body weight gain and survival, as well as normalized psychosine levels in the brain.