To clinically diagnose MM2-cortical (MM2C) and MM2-thalamic (MM2T)-type sporadic Creutzfeldt-Jakob disease (sCJD) at early stage with high sensitivity and specificity.
We reviewed the results of ...Creutzfeldt-Jakob disease Surveillance Study in Japan between April 1999 and September 2019, which included 254 patients with pathologically confirmed prion diseases, including 9 with MM2C-type sCJD (MM2C-sCJD) and 10 with MM2T-type sCJD (MM2T-sCJD), and 607 with non-prion diseases.
According to the conventional criteria of sCJD, 4 of 9 patients with MM2C- and 7 of 10 patients with MM2T-sCJD could not be diagnosed with probable sCJD until their death. Compared with other types of sCJD, patients with MM2C-sCJD showed slower progression of the disease and cortical distribution of hyperintensity lesions on diffusion-weighted images of brain MRI. Patients with MM2T-sCJD also showed relatively slow progression and negative results for most of currently established investigations for diagnosis of sCJD. To clinically diagnose MM2C-sCJD, we propose the new criteria; diagnostic sensitivity and specificity to distinguish 'probable' MM2C-sCJD from other subtypes of sCJD, genetic or acquired prion diseases and non-prion disease controls were 77.8% and 98.5%, respectively. As for MM2T-sCJD, clinical and laboratory features are not characterised enough to develop its diagnostic criteria.
MM2C-sCJD can be diagnosed at earlier stage using the new criteria with high sensitivity and specificity, although it is still difficult to diagnose MM2T-sCJD clinically.
Pathological hallmark of Alzheimer’s disease (AD) is characterized by the accumulation and aggregation of amyloid β (Aβ) peptides into extracellular plaques of the brain. Clarification of the process ...of how soluble Aβ starts to assemble into amyloid fibrils is an essential step in elucidating the pathogenesis of AD. In our previous study, Aβ proteoforms including full-length Aβ40 and Aβ42/43 with N- and C-terminal truncated forms were visualized in postmortem brains from AD patients with matrix-assisted laser desorption/ionization-based mass spectrometry imaging (MALDI-MSI). In this study, Aβ proteoforms were consistently visualized by an updated protocol, and uncharacterized peptides such as Aβ1-29 and Aβ10-40 in AD brains were also visualized. To decipher neurotoxic effects of Aβ in patients’ brains, here we integrate liquid chromatography tandem mass spectrometry (LC-MS/MS) based shotgun proteomics with laser microdissection (LMD) excised tissue samples as well as direct tissue imaging with MALDI-MSI. With this approach, we have highlighted dynamic alterations of microtubule associating proteins (MAPs) including MAP1A, MAP1B and MAP2 as well as AD dominant proteins including APP, UCHL1, SNCA, and APOE. Of note, as lipid dysregulation has been implicated with AD pathology, we have challenged to integrate proteomics and lipid imaging for AD and control brain tissue. Spatial multi-omics is also valid to uncover molecular pathology of white matter as well as grey matter and leptomeningeal area, for example, by visualizing heme in patients’ postmortem brains.
Autoantibodies to muscle-specific tyrosine kinase (MuSK) proteins at the neuromuscular junction (NMJ) cause refractory generalized myasthenia gravis (MG) with dyspnea more frequently than other MG ...subtypes. However, the mechanisms via which MuSK, a membrane protein locally expressed on the NMJ of skeletal muscle, is supplied to the immune system as an autoantigen remains unknown. Here, we identified MuSK in both mouse and human serum, with the amount of MuSK dramatically increasing in mice with motor nerve denervation and in MG model mice. Peptide analysis by liquid chromatography-tandem-mass spectrometry (LC-MS/MS) confirmed the presence of MuSK in both human and mouse serum. Furthermore, some patients with MG have significantly higher amounts of MuSK in serum than healthy controls. Our results indicated that the secretion of MuSK proteins from muscles into the bloodstream was induced by ectodomain shedding triggered by neuromuscular junction failure. The results may explain why MuSK-MG is refractory to treatments and causes rapid muscle atrophy in some patients due to the denervation associated with Ab-induced disruption of neuromuscular transmission at the NMJ. Such discoveries pave the way for new MG treatments, and MuSK may be used as a biomarker for other neuromuscular diseases in preclinical studies, clinical diagnostics, therapeutics, and drug discovery.
•Matrix protease releases ectodomain of MuSK from C2C12 cells.•The MuSK ectodomain in both human and mouse serum was identified by mass spectrometry.•Serum MuSK levels accurately reflect the degree of nerve denervation and reinnervation.•MuSK protein levels increased in the serum of EAMG mice and some patients with MG.•MuSK could potentially be used as a biomarker for other neuromuscular diseases.
Objective
Amyloid-β plaques and neurofibrillary tangles composed of tau protein are the neuropathological hallmarks of Alzheimer’s disease. In recent years, marked progress has been made in ...Alzheimer’s disease research using tau ligands for positron emission tomography (PET). However, the issue of off-target binding, that is, the binding of ligands to regions without tau pathology, remains unresolved. Tissues with melanin-containing cells (MCCs) have been suggested as binding targets for tau ligands. In the present study, we characterized the MCC-binding properties of representative tau PET ligands.
Methods
Autoradiographic studies of
18
FAV-1451 and
18
FTHK5351 were conducted using postmortem human midbrain sections. Saturation-binding assays of
18
FAV-1451 and
18
FTHK5351 were performed with B16F10 melanoma cells. The blocking effects of 25 compounds against
18
FTHK5351 binding to B16F10 cells were used to investigate the relationship between chemical structure and MCC binding.
Results
Autoradiography demonstrated specific binding of the radioligands in the substantia nigra.
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FAV-1451 and
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FTHK5351 exhibited saturable binding to melanoma cells (
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FAV-1451:
K
d
= 669 ± 196 nM,
B
max
= 622 ± 269 pmol/mg protein;
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FTHK5351:
K
d
= 441 ± 126 nM,
B
max
= 559 ± 75.5 pmol/mg protein). In blocking studies with melanoma cells, compounds bearing multiple aromatic rings and an aminopyridine group, including tau ligands such as AV-1451, PBB3, and a lead compound of MK-6240, exhibited the inhibition of
18
FTHK5351 binding comparable to self-blocking by THK5351 (> 70% at 10 µM).
Conclusions
These studies suggest that the binding properties of
18
FAV-1451 and
18
FTHK5351 are sufficient to expect highlighting of tissues with a high density of MCCs. The findings of the present study should aid the development of neuroimaging ligands that do not bind to MCC.
We herein report a case of cerebral infarct in a patient with coronavirus disease 2019 (COVID-19) infection who died of aspiration pneumonia. The postmortem examination of the brain revealed embolic ...infarct with negative findings on quantitative reverse transcription polymerase chain reaction (qRT-PCR) as well as immunohistochemistry to detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The systemic examination only revealed low copy numbers of SARS-CoV-2 in the bronchus. This is the first and so far only autopsy case of COVID-19 infection with pathologic and virologic findings of the postmortem brain in Japan.
Erdheim-Chester disease (ECD) is a rare, non-Langerhans cell histiocytosis characterized by the infiltration of foamy histiocytes into multiple organs. We herein report a case of ECD with central ...nervous system (CNS) involvement in a 63-year-old man who also presented a positive result for Toxoplasma gondii nested polymerase chain reaction testing of cerebrospinal fluid. Since anti-Toxoplasma treatment proved completely ineffective, we presumed latent infection of the CNS with T. gondii. This case suggests the difficulty of distinguishing ECD with CNS involvement from toxoplasmic encephalitis and the possibility of a relationship between the pathogeneses of ECD and infection with T. gondii.
Neurodegenerative diseases involving protein aggregation often accompany psychiatric symptoms. Frontotemporal lobar degeneration (FTLD) associated with TAR DNA-binding protein 43 (TDP-43) aggregation ...is characterized by progressive neuronal atrophy in frontal and temporal lobes of cerebral cortex. Furthermore, patients with FTLD display mental dysfunction in multiple behavioral dimensions. Nevertheless, their molecular origin for psychiatric symptoms remains unclear.
In FTLD neurons and mouse models with TDP-43 aggregates, we examined coaggregation between TDP-43 and disrupted in schizophrenia 1 (DISC1), a key player in the pathology of mental conditions and its effects on local translation in dendrites and psychiatric behaviors. The protein coaggregation and the expression level of synaptic proteins were also investigated with postmortem brains from patients with FTLD (n = 6).
We found cytosolic TDP-43/DISC1 coaggregates in brains of both FTLD mouse model and patients with FTLD. At the mechanistic levels, the TDP-43/DISC1 coaggregates disrupted the activity-dependent dendritic local translation through impairment of translation initiation and, in turn, reduced synaptic protein expression. Behavioral deficits detected in FTLD model mice were ameliorated by exogenous DISC1 expression.
Our findings reveal a novel role of the aggregate-prone TDP-43/DISC1 protein complex in regulating local translation, which affects aberrant behaviors relevant to multiple psychiatric dimensions.
Depression is one of the common psychiatric disorders in old age. Major depressive disorder (MDD) has been identified as a risk factor or prodrome for neurodegenerative dementias, suggesting ...neuropathological overlaps and a continuum between MDD and neurodegenerative disorders. In this study, we examined tau and amyloid-β (Aβ) accumulations in the brains of MDD and healthy controls using positron emission tomography (PET) to explore pathological substrates of this illness. Twenty MDD and twenty age-matched, healthy controls were examined by PET with a tau radioligand,
CPBB3, and an Aβ radioligand,
CPiB. Radioligand retentions were quantified as a standardized uptake value ratio (SUVR). We also assessed clinical manifestations of the patients using the 17-item Hamilton Depression Scale, the Geriatric Depression Scale, and psychotic symptoms. Mean cortical
CPBB3 SUVRs in MDD patients were significantly higher than those of healthy controls. These values were higher in MDD patients with psychotic symptoms than in those without any. The present findings indicate that tau depositions may underlie MDD, and especially in patients with psychotic symptoms. PET detection of tau accumulations may provide mechanistic insights into neuronal dysfunctions in these cases and could serve as predictions of their clinical consequences.
Progressive multifocal leukoencephalopathy (PML) is a fatal disease caused by John Cunningham virus (JCV) infection; however, a growing number of PML patients now survive longer and achieve ...remission, largely due to the advent of combination antiretroviral therapy. Several reports have suggested that the pathology in such patients presents only chronic demyelination without characteristic cellular changes, being referred to as “burnt‐out” PML. On the other hand, our knowledge of “burnt‐out” PML is still substantially limited, especially in patients with non‐human immunodeficiency virus infection. Here, we report a case of PML associated with idiopathic CD4+ lymphocytopenia (ICL) who presented with spontaneous remission and survived for 11 years after onset. Notably, postmortem examination revealed surprisingly broad “burnt‐out” lesions lacking the classic histopathological findings. However, pathogenic JCV‐specific DNA sequences was still present in the autopsied brain tissue. This case suggests that complete remission can be achieved with a persistent presence of JCV‐specific pathogenic sequences, even after a catastrophic infection. Considering that there have been a few reported cases of PML with ICL with long survival, the long‐term survival of our case may share a favorable immunological response that is unique to a subgroup of ICL.
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with marked variety in its clinical manifestations. While characteristic neuroimaging and skin biopsy findings are ...important clues to the diagnosis, autopsy studies are still important for confirming the exact disease features. We herein report the case of a patient who received an antemortem diagnosis of familial NIID with dementia-dominant phenotype that was later confirmed by an autopsy. Our report is the first to document a case of autopsy-confirmed NIID involving both cognitive impairment and sensorimotor neuropathy.
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