OUR PUBLICATIONS

Most Recent Publications

Last updated May 3, 2024




Lee S, Kovacs GG. The Irony of Iron: The Element with Diverse Influence on Neurodegenerative Diseases. Int J Mol Sci. 2024 Apr 12;25(8):4269. doi: 10.3390/ijms25084269. PMID: 38673855. Review.

Here, we review the major proteinopathy-specific observations supporting four distinct hypotheses: (1) iron deposition is a consequence of protein pathology; (2) iron promotes protein pathology; (3) iron protects from or hinders protein pathology; and (4) deposition of iron and protein pathology contribute parallelly to pathogenesis. Iron is an essential element for physiological brain function, requiring a fine balance of its levels. Understanding of disease-related iron accumulation at a more intricate and systemic level is critical for advancements in iron chelation therapies.

Yoshida K, Forrest SL, Ichimata S, Tanaka H, Kon T, Tartaglia MC, Tator CH, Lang AE, Nishida N, Kovacs GG. Revisiting the relevance of Hirano bodies in neurodegenerative diseases. Neuropathol Appl Neurobiol. 2024 Apr;50(2):e12978. doi: 10.1111/nan.12978. PMID: 38634242

Hirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases. The study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.

Kon T, Lee S, Martinez-Valbuena I, Yoshida K, Tanikawa S, Lang AE, Kovacs GG. Molecular Behavior of α-Synuclein Is Associated with Membrane Transport, Lipid Metabolism, and Ubiquitin-Proteasome Pathways in Lewy Body Disease. Int J Mol Sci. 2024 Feb 26;25(5):2676. doi: 10.3390/ijms25052676. PMID: 38473923.

Kon T, Forrest SL, Lee S, Martinez-Valbuena I, Li J, Nassir N, Uddin MJ, Lang AE, Kovacs GG. Neuronal SNCA transcription during Lewy body formation. Acta Neuropathol Commun. 2023 Nov 23;11(1):185. doi: 10.1186/s40478-023-01687-7. PMID: 37996943.  

We evaluated the total cell body, nuclear, and cytoplasmic area density of SNCA transcripts in neurons without and with various α-syn immunoreactive cytopathologies in the substantia nigra and amygdala in autopsy cases of LBD, using RNAscope combined with immunofluorescence for disease-associated α-syn. Our observations inform therapy development focusing on targeting SNCA transcription in LBD.

Kim A, Martinez-Valbuena I, Keith JL, Kovacs GG, Lang AE. Misfolded α-Synuclein Seeding Is Detected in Suspected LRRK2-Parkinson's Disease without Immunohistochemically Detectable α-Synuclein Pathology. Mov Disord. 2023 Nov 20. doi: 10.1002/mds.29665. PMID: 37986700. 

Tanaka H, Martinez-Valbuena I, Forrest SL, Couto B, Reyes NG, Morales-Rivero A, Lee S, Li J, Karakani AM, Tang-Wai DF, Tator C, Khadadadi M, Sadia N, Tartaglia MC, Lang AE, Kovacs GG. Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy. Brain. 2023 Nov 16:awad381. doi: 10.1093/brain/awad381. PMID: 37972275.  

To characterize the involvement of the peripheral nervous system (PNS) in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. We concluded that prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

Martinez-Valbuena I, Lee S, Santamaria E, Irigoyen JF, Forrest S, Li J, Tanaka H, Couto B, Reyes NG, Qamar H, Karakani AM, Kim A, Senkevich K, Rogaeva E, Fox SH, Tartaglia C, Visanji NP, Andrews T, Lang AE, Kovacs GG. 4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy. bioRxiv. 2023 Sep 29:2023.09.28.559953. doi: 10.1101/2023.09.28.559953. PMID: 37808843.

We performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. Our observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

Ichimata S, Yoshida K, Li J, Rogaeva E, Lang AE, Kovacs GG. The molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease. Brain Pathol. 2024 Jan;34(1):e13210. doi: 10.1111/bpa.13210. Epub 2023 Aug 31. PMID: 37652560.

We investigated the molecular spectrum of amyloid-beta (Aβ) in neurodegenerative diseases beyond Alzheimer's disease. Our data suggest that the type of concomitant proteinopathies influences the spectrum of Aβ deposition, impacted also by sex and APOE genotypes.

Ichimata S, Martinez-Valbuena I, Lee S, Li J, Karakani AM, Kovacs GG. Distinct Molecular Signatures of Amyloid-Beta and Tau in Alzheimer’s Disease Associated with Down Syndrome. Int. J. Mol. Sci. 2023, 24, 11596. https://doi.org/10.3390/ijms241411596

We performed comprehensive immunohistochemistry using antibodies recognizing eight different epitopes of Aβ and six different pathological tau epitopes in a series of ten Down syndrome (DS) and ten sporadic Alzheimer's disease (sAD) cases. Based on the findings, we suggest that the Aβ and tau molecular signatures in DS are distinct from those in sAD.

Kim A, Martinez-Valbuena I, Li J, Lang AE, Kovacs GG. Disease-Specific α-Synuclein Seeding in Lewy Body Disease and Multiple System Atrophy Are Preserved in Formaldehyde-Fixed Paraffin-Embedded Human Brain. Biomolecules. 2023 Jun 2;13(6):936. doi: 10.3390/biom13060936. PMID: 37371515; PMCID: PMC10296376.

Our recent publication presents a novel method in extracting proteins from formalin-fixed paraffin-embedded archived human brain tissue and demonstrates disease-specific alpha-synuclein seeding differences between MSA and PD.

Forrest SL, Lee S, Nassir N, Martinez-Valbuena I, Sackmann V, Li J, Ahmed A, Tartaglia CM, Ittner LM, Lang AE, Uddin M, Kovacs GG. Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in Progressive Supranuclear Palsy. Acta Neuropathol. 2023;10.1007/s00401-023-02604-x. doi:10.1007/s00401-023-02604-x

We have just published a paper in Acta Neuropathologica on RNA detection in the neurodegenerative disease, progressive supranuclear palsy (PSP). We are the first to demonstrate with different methods that in addition to neurons, MAPT RNA is consistently expressed in glia. MAPT RNA expression varies between and within cell types even in the same anatomical area and MAPT expression is preserved in neurons and glia with pathological tau aggregates.

Findings from this study have relevance for the development of a dual approach to tau-based therapies in neurodegenerative diseases. Firstly, we can propose to apply therapies that decrease the expression of RNA responsible to produce physiological tau protein - we aim not to feed the process of transforming the good tau to bad tau protein. Secondly, we can propose to target the bad protein itself. We suggest that probably it is better to target both aspects instead of only one.

Ichimata S, Kim A, Nishida N, Kovacs GG. Lack of difference between amyloid-beta burden at gyral crests and sulcal depths in diverse neurodegenerative diseases. Neuropathol Appl Neurobiol. 2022 Dec 17:e12869. doi: 10.1111/nan.12869. Epub ahead of print. PMID: 36527296.

We show that Aβ is almost evenly distributed in both gyral crests and sulcal depths in the frontal and temporal lobes from the early stage, in diverse neurodegenerative diseases.

Ichimata S, Martinez-Valbuena I, Forrest SL, Kovacs GG. Expanding the spectrum of amyloid-β plaque pathology: the Down syndrome associated 'bird-nest plaque'. Acta Neuropathol. 2022 Dec;144(6):1171-1174. doi: 10.1007/s00401-022-02500-w. Epub 2022 Sep 16. PMID: 36112224.

We identified an unusual morphological form of Aβ plaques reminiscent of a bird-nest in individuals with Down syndrome (DS). We suggest that the presence of the 'bird-nest plaque ' (BNP), particularly typical BNPs, in the temporal cortex can be suggestive of DS-related Alzheimer's disease pathology and indicate more accelerated Aβ accumulation.


Lee S, Martinez-Valbuena I, de Andrea CE, Villalba-Esparza M, Ilaalagan S, Couto B, Visanji NP, Lang AE, Kovacs GG. Cell-Specific Dysregulation of Iron and Oxygen Homeostasis as a Novel Pathophysiology in PSP. Ann Neurol. 2022 Oct 30. doi: 10.1002/ana.26540. Epub ahead of print. PMID: 36309960.

Iron accumulation is seen in early-affected regions of PSP brains. We for the first time examined the pathological iron burden at the cellular level and discovered key cell population accumulating iron in human PSP brains. Parallelly, we found dysregulated oxygen dysregulation and expression changes of unique group of iron-related genes in the same regions. Our discovery will help the understanding of early PSP pathways and inform efforts on iron chelation therapies at the cellular level.

Forrest SL, Tartaglia MC, Kim A, Alcaide-Leon P, Rogaeva E, Lang A, Kovacs GG. Progressive Supranuclear Palsy Syndrome Associated With a Novel Tauopathy: Case Study. Neurology. 2022 Oct 3:10.1212/WNL.0000000000201485. doi: 10.1212/WNL.0000000000201485. Epub ahead of print. PMID: 36192179.

Here we report a novel tauopathy in a patient with protracted course progressive supranuclear. This study also suggests that memory deficit and hippocampal atrophy may be suggestive of non-AD-type pathology, including limbic-predominant neuronal inclusion body tauopathy (LNT). Understanding the diverse range of tau pathology may help explain the phenotypic diversity seen in PSP patients.

Martinez-Valbuena I, Kovacs GG, Lang AE. Extracellular vesicles and seeding amplification: a step closer to a Parkinson's disease blood test. Brain. 2022 Sep 14;145(9):2946-2948. doi: 10.1093/brain/awac292. PMID: 35943843.


Forrest SL, Wagner S, Kim A, Kovacs GG. Association of glial tau pathology and LATE-NC in the ageing brain. Neurobiol Aging. 2022 Nov;119:77-88. doi: 10.1016/j.neurobiolaging.2022.07.010. Epub 2022 Jul 31. PMID: 35977443.

We performed systematic anatomical mapping of a range of pathologies in an unselected European community-dwelling ageing cohort. This study shows interactions and convergence of medial temporal pathologies, suggesting overlapping pathogenesis that might include barrier dysfunction.  This study broadens the spectrum of age-related pathologies and highlights a novel ageing-related tau pathology in oligodendroglia.

Martinez-Valbuena I, Swinkin E, Santamaria E, Fernandez-Irigoyen J, Sackmann V, Kim A, Li J, Gonzalez-Latapi P, Kuhlman G, Bhowmick SS, Visanji NP, Lang AE, Kovacs GG. α-Synuclein molecular behavior and nigral proteomic profiling distinguish subtypes of Lewy body disorders. Acta Neuropathol. 2022 Aug;144(2):167-185. doi: 10.1007/s00401-022-02453-0. Epub 2022 Jun 24. PMID: 35748929.

In this publication we show a proof of concept that if you do a molecular characterization of LBD, you can find subgroups of patients that you cannot find with conventional techniques. Lewy body disorders (LBD) are clinically very heterogenous and encompass Parkinson’s disease and dementia with Lewy bodies, two of the most prevalent neurodegenerative diseases. Currently, no treatment can reverse or stop the progression of Lewy body disorders. We also hope that, similarly to the progress made in developing treatments for specific types of cancer, subtypes of Lewy body disorders will help us create personalized medicine strategies for these disorders.

Ichimata S, Yoshida K, Visanji NP, Lang AE, Nishida N, Kovacs GG. Patterns of Mixed Pathologies in Down Syndrome. J Alzheimers Dis. 2022;87(2):595-607. doi: 10.3233/JAD-215675. PMID: 35311708.

We find that Down syndrome is a complex multi-proteinopathy exhibiting subtle deviations from Alzheimer's disease.

Martinez-Valbuena I, Visanji NP, Olszewska DA, Sousa M, Bhakta P, Vasilevskaya A, Anastassiadis C, Tartaglia MC, Kovacs GG, Lang AE. Combining Skin α-Synuclein Real-Time Quaking-Induced Conversion and Circulating Neurofilament Light Chain to Distinguish Multiple System Atrophy and Parkinson's Disease. Mov Disord. 2022 Mar;37(3):648-650. doi: 10.1002/mds.28912. Epub 2022 Jan 12. PMID: 35019153.

This study has enabled us to stablish the RT-QuIC assay as a tool to detect α-synuclein seeding activity not only in samples derived from post-mortem brain tissue, but also in the skin and cerebrospinal fluid of people diagnosed with Parkinson’s disease, multiple system atrophy or progressive supranuclear palsy. Our research showed that the RT-QuIC assay is able to detect cutaneous α-synuclein seeding activity in both multiple system atrophy and Parkinson’s disease with high sensitivity and specificity compared with patients with progressive supranuclear palsy and healthy control subjects.