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Cureus Oct 2023A three-year-old female patient was admitted to our institution due to subacute fever, intermittent vomiting, persistent bilateral mydriasis after cycloplegia, right...
A three-year-old female patient was admitted to our institution due to subacute fever, intermittent vomiting, persistent bilateral mydriasis after cycloplegia, right central facial palsy, and mild right hemiparesis with hyperreflexia. Brain MRI shows encephalitis in frontal, parietal, insular, and left putamen course and loss of cortical volume and white matter of the entire left hemisphere which are features described in Rasmussen's encephalitis (RE). Therapy with intravenous methylprednisolone bolus was initiated, with adequate clinical response. We consider in this case the diagnosis of atypical RE by imaging criteria in the subacute stage. There are few reports of atypical RE without epilepsy or continuous partial epilepsy. Our purpose is to present a case of a patient with RE images without epilepsy seizures and review the diagnostic and therapeutic approach of RE.
PubMed: 37808599
DOI: 10.7759/cureus.46647 -
Acta Neuropathologica Aug 2023Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in...
Two siblings with deletion mutation ∆K281 in MAPT developed frontotemporal dementia. At autopsy, numerous inclusions of hyperphosphorylated 3R Tau were present in neurons and glial cells of neocortex and some subcortical regions, including hippocampus, caudate/putamen and globus pallidus. The inclusions were argyrophilic with Bodian silver, but not with Gallyas-Braak silver. They were not labelled by an antibody specific for tau phosphorylated at S262 and/or S356. The inclusions were stained by luminescent conjugated oligothiophene HS-84, but not by bTVBT4. Electron cryo-microscopy revealed that the core of tau filaments was made of residues K254-F378 of 3R Tau and was indistinguishable from that of Pick's disease. We conclude that MAPT mutation ∆K281 causes Pick's disease.
Topics: Humans; Pick Disease of the Brain; Silver; tau Proteins; Frontotemporal Dementia; Neurons; Mutation
PubMed: 37351604
DOI: 10.1007/s00401-023-02598-6 -
Nature Communications Jul 2023The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant...
The ability to use blood to predict the outcomes of Parkinson's disease, including disease progression and cognitive and motor complications, would be of significant clinical value. We undertook bulk RNA sequencing from the caudate and putamen of postmortem Parkinson's disease (n = 35) and control (n = 40) striatum, and compared molecular profiles with clinical features and bulk RNA sequencing data obtained from antemortem peripheral blood. Cognitive and motor complications of Parkinson's disease were associated with molecular changes in the caudate (stress response) and putamen (endothelial pathways) respectively. Later and earlier-onset Parkinson's disease were molecularly distinct, and disease duration was associated with changes in caudate (oligodendrocyte development) and putamen (cellular senescence), respectively. Transcriptome patterns in the postmortem Parkinson's disease brain were also evident in antemortem peripheral blood, and correlated with clinical features of the disease. Together, these findings identify molecular signatures in Parkinson's disease patients' brain and blood of potential pathophysiologic and prognostic importance.
Topics: Humans; Parkinson Disease; Transcriptome; Brain; Corpus Striatum; Putamen
PubMed: 37407548
DOI: 10.1038/s41467-023-39652-6 -
Nature Communications Nov 2023The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in...
The degenerative process in Parkinson's disease (PD) causes a progressive loss of dopaminergic neurons (DaNs) in the nigrostriatal system. Resolving the differences in neuronal susceptibility warrants an amenable PD model that, in comparison to post-mortem human specimens, controls for environmental and genetic differences in PD pathogenesis. Here we generated high-quality profiles for 250,173 cells from the substantia nigra (SN) and putamen (PT) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian macaques and matched controls. Our primate model of parkinsonism recapitulates important pathologic features in nature PD and provides an unbiased view of the axis of neuronal vulnerability and resistance. We identified seven molecularly defined subtypes of nigral DaNs which manifested a gradient of vulnerability and were confirmed by fluorescence-activated nuclei sorting. Neuronal resilience was associated with a FOXP2-centered regulatory pathway shared between PD-resistant DaNs and glutamatergic excitatory neurons, as well as between humans and nonhuman primates. We also discovered activation of immune response common to glial cells of SN and PT, indicating concurrently activated pathways in the nigrostriatal system. Our study provides a unique resource to understand the mechanistic connections between neuronal susceptibility and PD pathophysiology, and to facilitate future biomarker discovery and targeted cell therapy.
Topics: Animals; Humans; Mice; Parkinson Disease; Parkinsonian Disorders; Substantia Nigra; Dopaminergic Neurons; Macaca; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Disease Models, Animal; Mice, Inbred C57BL
PubMed: 37980356
DOI: 10.1038/s41467-023-43213-2 -
Human Brain Mapping Dec 2023Atrophy related to multiple sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative...
Atrophy related to multiple sclerosis (MS) has been found at the early stages of the disease. However, the archetype dynamic trajectories of the neurodegenerative process, even prior to clinical diagnosis, remain unknown. We modeled the volumetric trajectories of brain structures across the entire lifespan using 40,944 subjects (38,295 healthy controls and 2649 MS patients). Then, we estimated the chronological progression of MS by assessing the divergence of lifespan trajectories between normal brain charts and MS brain charts. Chronologically, the first affected structure was the thalamus, then the putamen and the pallidum (around 4 years later), followed by the ventral diencephalon (around 7 years after thalamus) and finally the brainstem (around 9 years after thalamus). To a lesser extent, the anterior cingulate gyrus, insular cortex, occipital pole, caudate and hippocampus were impacted. Finally, the precuneus and accumbens nuclei exhibited a limited atrophy pattern. Subcortical atrophy was more pronounced than cortical atrophy. The thalamus was the most impacted structure with a very early divergence in life. Our experiments showed that lifespan models of most impacted structures could be an important tool for future preclinical/prodromal prognosis and monitoring of MS.
Topics: Humans; Multiple Sclerosis; Longevity; Magnetic Resonance Imaging; Brain; Atrophy; Gray Matter
PubMed: 37615064
DOI: 10.1002/hbm.26464 -
BioRxiv : the Preprint Server For... Aug 2023Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous...
Age is a major common risk factor underlying neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Previous studies reported that chronological age correlates with differential gene expression across different brain regions. However, prior datasets have not disambiguated whether expression associations with age are due to changes in cell numbers and/or gene expression per cell. In this study, we leveraged single nucleus RNA-sequencing (snRNAseq) to examine changes in cell proportions and transcriptomes in four different brain regions, each from 12 donors aged 20-30 years (young) or 60-85 years (old). We sampled 155,192 nuclei from two cortical regions (entorhinal cortex and middle temporal gyrus) and two subcortical regions (putamen and subventricular zone) relevant to neurodegenerative diseases or the proliferative niche. We found no changes in cellular composition of different brain regions with healthy aging. Surprisingly, we did find that each brain region has a distinct aging signature, with only minor overlap in differentially associated genes across regions. Moreover, each cell type shows distinct age-associated expression changes, including loss of protein synthesis genes in cortical inhibitory neurons, axonogenesis genes in excitatory neurons and oligodendrocyte precursor cells, enhanced gliosis markers in astrocytes and disease-associated markers in microglia, and genes critical for neuron-glia communication. Importantly, we find cell type-specific enrichments of age associations with genes nominated by Alzheimer's disease and Parkinson's disease genome-wide association studies (GWAS), such as apolipoprotein E (), and leucine-rich repeat kinase 2 () in microglia that are independent of overall expression levels across cell types. We present this data as a new resource which highlights, first, region- and cell type-specific transcriptomic changes in healthy aging that may contribute to selective vulnerability and, second, provide context for testing GWAS-nominated disease risk genes in relevant subtypes and developing more targeted therapeutic strategies. The data is readily accessible without requirement for extensive computational support in a public website, https://brainexp-hykyffa56a-uc.a.run.app/.
PubMed: 37577533
DOI: 10.1101/2023.07.31.551097 -
NPJ Parkinson's Disease Oct 2023Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD)....
Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson's disease (PD). However, it's unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (K), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen's d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (-67%) and posterolateral SNc (-11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA K (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA K loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.
PubMed: 37852988
DOI: 10.1038/s41531-023-00586-x