BACKGROUND: TAR DNA-Binding Protein 43 (TDP-43) pathological inclusions are a distinctive feature in dozens of neurodegenerative pathologies, including limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Prior investigations identified vascular-associated TDP-43-positive micro-lesions, known as \"Lin bodies,\" located on or near the brain capillaries of some individuals with LATE-NC. This study aimed to investigate the relationship between the accumulation of Lin bodies and glial cells in LATE-NC and the potential co-localization with ferritin, a protein associated with iron storage. Using multiplexed immunohistochemistry and digital pathology tools, we conducted pathological analyses to investigate the relationship between Lin bodies and glial markers (GFAP for astrocytes, IBA1 for microglia) and ferritin. Analyses were conducted on post-mortem brain tissues collected from individuals with pathologically confirmed Alzheimer\'s disease neuropathological changes (ADNC) and LATE-NC.
RESULTS: As shown previously, there was a robust association between Lin bodies and GFAP-positive astrocyte processes. Moreover, we also observed Lin bodies frequently co-localizing with ferritin, suggesting a potential link to compromised vascular integrity. Subsequent analyses demonstrated increased astrocytosis near Lin body-positive vessels compared to those without Lin bodies, particularly in ADNC cases. These results suggest that the accumulation of Lin bodies may elicit an increased glial response, particularly among astrocytes, possibly related to impaired vascular integrity.
CONCLUSIONS: Lin bodies are associated with a local reactive glial response. The strong association of Lin bodies with ferritin suggests that the loss of vascular integrity may be either a cause or a consequence of the pTDP-43 pathology. The reactive glia surrounding the affected vessels could further compromise vascular function.

BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally.
METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression (\'spreading patterns\') of motor deficits in a cohort of 910 ALS patients in Germany.
RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region.
CONCLUSIONS: Our results indicate that, although the phenotype of so-called \'spinal\' or \'intraspinal\' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a \'spinal\' or an \'intraspinal\' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.

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Pathogenic mutations of transactivation response element DNA-binding protein 43 (TDP-43) are closely linked with amyotrophic lateral sclerosis (ALS). It was recently reported that two ALS-linked familial mutants A315T and A315E of TDP-43307-319 peptides can self-assemble into oligomers including tetramers, hexamers, and octamers, among which hexamers were suggested to form the β-barrel structure. However, due to the transient nature of oligomers, their conformational properties and the atomic mechanisms underlying the β-barrel formation remain largely elusive. Herein, we investigated the hexameric conformational distributions of the wild-type (WT) TDP-43307-319 fragment and its A315T and A315E mutants by performing all-atom explicit-solvent replica exchange with solute tempering 2 simulations. Our simulations reveal that each peptide can self-assemble into diverse conformations including ordered β-barrels, bilayer β-sheets and/or monolayer β-sheets, and disordered complexes. A315T and A315E mutants display higher propensity to form β-barrel structures than the WT, which provides atomic explanation for their enhanced neurotoxicity reported previously. Detailed interaction analysis shows that A315T and A315E mutations increase inter-molecular interactions. Also, the β-barrel structures formed by the three different peptides are stabilized by distinct inter-peptide side-chain hydrogen bonding, hydrophobic, and aromatic stacking interactions. This study demonstrates the enhanced β-barrel formation of the TDP-43307-319 hexamer by the pathogenic A315T and A315E mutations and reveals the underlying molecular determinants, which may be helpful for in-depth understanding of the ALS-mutation-induced neurotoxicity of TDP-43 protein.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a recently described neuropathological construct associated with dementia. This study aimed to investigate in an autopsy study, LATE-NC and its associations with potential estrogen-related risk factors collected about 30 years before death. Participants were part of The 90+ Study and had, as part of the Leisure World Cohort Study, provided information on menstrual and reproductive variables and details of use of estrogen replacement therapy (ERT). No menstrual and reproductive variable showed an association with LATE-NC. Use of ERT, especially long-term use (15+ years) and more recent use (within 1 year of completing the questionnaire), was associated with reduced risk. The odds were significantly lower for long-term (0.39, 95% confidence interval [CI]: 0.16-0.95) and recent use (0.39, 95% CI: 0.16-0.91) compared with no use. In conclusion, we found that women who reported long-term ERT in their 50s and 60s had a significantly reduced odds of harboring LATE-NC when they died in the 10th and 11th decades of their lives. Our study adds to the existing literature reporting seemingly protective effect of peri- and postmenopausal ERT against neurodegenerative dementia.

Blood-based biomarkers provide a crucial information in the progress of neurodegenerative diseases with a minimally invasive sampling method. Validated blood-based biomarker application in people with amyotrophic lateral sclerosis would derive numerous benefits. Canine degenerative myelopathy is a naturally occurring animal disease model to study the biology of human amyotrophic lateral sclerosis. Serum derived exosomes are potential carriers for cell-specific cargoes making them ideal venue to study biomarkers for a variety of diseases and biological processes. This study assessed the exosomal proteins that may be assigned as surrogate biomarker that may reflect biochemical changes in the central nervous system.
Exosomes were isolated from canine serum using commercial exosome isolation reagents. Exosomes target proteins contents were analyzed by the Western blotting method.
The profiles of potential biomarker candidates in spinal cord homogenate and that of serum-derived exosomes were found elevated in dogs with degenerative myelopathy as compared to control subjects.
Serum-derived exosomal biomolecules can serve as surrogate biomarkers in neurodegenerative diseases.KEY MESSAGESA canine with degenerative myelopathy can serve as a model animal to study human amyotrophic lateral sclerosis.Serum-derived exosomes contain Transactive Response DNA Binding Protein 43 (TDP-43), a potential biomarker candidate.The levels of spinal cord TDP-43 proteins and that of serum-derived exosomes exhibited similar profiling. Therefore, serum derived exosomes may be used as a venue for establishing blood-based biomarkers for neurodegenerative diseases.

The low complexity domain (LCD) sequence has been defined in terms of entropy using a 12 amino acid sliding window along a protein sequence in the study of disease-related genes. The amyotrophic lateral sclerosis (ALS)-related TDP-43 protein sequence with intra-LCD structural information based on cryo-EM data was published recently. An application of entropy and Higuchi fractal dimension calculations was described using the Znf521 and HAR1 sequences. A computational analysis of the intra-LCD sequence entropy and Higuchi fractal dimension values at the amino acid level and at the ATCG nucleotide level were conducted without the sliding window requirement. The computational results were consistent in predicting the intermediate entropy/fractal dimension value produced when two subsequences at two different entropy/fractal dimension values were combined. The computational method without the application of a sliding-window was extended to an analysis of the recently reported virulent genes-Orf6, Nsp6, and Orf7a-in SARS-CoV-2. The relationship between the virulence functionality and entropy values was found to have correlation coefficients between 0.84 and 0.99, using a 5% uncertainty on the cell viability data. The analysis found that the most virulent Orf6 gene sequence had the lowest nucleotide entropy and the highest protein fractal dimension, in line with extreme value theory. The Orf6 codon usage bias in relation to vaccine design was discussed.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease with characteristic of progressive general muscle weakness and atrophy. ALS is still lack of efficient treatment and laboratory biomarkers. In this study, we longitudinally examined ALS patients\' peripheral blood to search potential biomarkers. 18 ALS patients aged between 20 and 65 years were recruited in a clinical trial and longitudinal plasma samples were obtained and analyzed at baseline, 1, 3, 6 and 12 months follow up. Neurofilament light chain (NFL), phosphorylated neurofilament heavy chain (pNFH) by ELISA and exosomal TAR DNA-binding protein-43 (TDP-43) ratio were measured by flow cytometry assay in isolated exosomes RESULTS: Exosomal TDP-43 ratio significantly changed in 3-month (increased 60.8 ± 18.9%, p = 0.0005) and 6-month (increased 60.2 ± 32.6%, p = 0.0291) follow-up and close to significance at 12-month follow-up (increased 12.8 ± 10.8%, p = 0.0524). When subclassifying patients into rapid and slow progression groups, NFL but not pNFH is significantly higher in the rapid progression group at baseline (22.74 ± 1.66 pg/mL vs. 43.96 ± 12.87 pg/mL, p = 0.0136) and at 3-month follow-up (28.40 ± 3.39 pg/mL vs. 40.33 ± 5.44 pg/mL, p = 0.0356).
CONCLUSIONS: In this study, we found exosomal TDP-43 ratio was increasing along with follow-up at 3 and 6 months and NFL levels in plasma was associated with rapid progression in ALS patients. In addition to NFL, exosomal TDP-43 ratio might be a potential candidate of biomarkers for ALS long-term follow-up studies.

Currently TAR DNA binding protein 43 (TDP-43) pathology, underlying Amyotrophic Lateral Sclerosis (ALS), remains poorly understood which hinders both clinical diagnosis and drug discovery efforts. To better comprehend the disease pathophysiology, positron emission tomography (PET) and multi-parametric magnetic resonance imaging (mp-MRI) provide a non-invasive mode to investigate molecular, structural, and neurochemical abnormalities in vivo. For the first time, we report the findings of a longitudinal PET-MR study in the TDP-43A315T ALS mouse model, investigating disease-related changes in the mouse brain. 2-deoxy-2-[18F]fluoro-D-glucose [18F]FDG PET showed significantly lowered glucose metabolism in the motor and somatosensory cortices of TDP-43A315T mice whereas metabolism was elevated in the region covering the bilateral substantia nigra, reticular and amygdaloid nucleus between 3 and 7 months of age, as compared to non-transgenic controls. MR spectroscopy data showed significant changes in glutamate + glutamine (Glx) and choline levels in the motor cortex and hindbrain of TDP-43A315T mice compared to controls. Cerebral blood flow (CBF) measurements, using an arterial spin labelling approach, showed no significant age- or group-dependent changes in brain perfusion. Diffusion MRI indices demonstrated transient changes in different motor areas of the brain in TDP-43A315T mice around 14 months of age. Cytoplasmic TDP-43 proteinaceous inclusions were observed in the brains of symptomatic, 18-month-old mice, but not in non-symptomatic transgenic or wild-type mice. Our results reveal that disease- and age-related functional and neurochemical alterations, together with limited structural changes, occur in specific brain regions of transgenic TDP-43A315T mice, as compared to their healthy counterparts. Altogether these findings shed new light on TDP-43A315T disease pathogenesis and may prove useful for clinical management of ALS.

Association between the transactive response DNA-binding protein of 43 kDa (TDP-43), its newly described types (type α/type β), and resilience to Alzheimer\'s disease neuropathological change (ADNC) defined as preservation of normal cognitive functioning despite advanced ADNC has been evaluated in this case-control study of 63 older adults. Twenty-one resilient to ADNC individuals were matched 1:2 to nonresilient (Alzheimer\'s dementia) using propensity scores, accounting for age at death, neuritic plaque density, and neurofibrillary tangle stage. Resilient and matched nonresilient participants were similar in terms of gender, apolipoprotein E ε4 carriership, education, occupation, AD, and other pathologies. Resilient participants had lower frequency of TDP-43 co-pathology compared to nonresilient (19% vs. 62%, p = 0.002). Among TDP-43-positive cases, TDP-43 type α inclusions were absent in resilient to ADNC participants and were dominant in matched nonresilient cases (65%, p = 0.03). TDP-43 and TDP-43 types appear to be one of the key pathological determinants of loss of cognitive resilience to ADNC and hence are important in the understanding of the clinical expression of ADNC.