Degeneration of neurons and circuits across the striatum shows stereotyped time-course and spatial topography patterns that are distinct for Huntington's disease, Parkinson's disease, or the ...Tauopathies. These patterns of neurodegeneration in humans have not yet been systematically related to developmental, connectional, cellular, and chemical factors studied in human and non-human primates, that may underlie potential differences in selective vulnerability across striatal sectors. Relating primate anatomy to human pathology could provide new venues for identifying molecular, cellular, and connectional factors linked to the degeneration of striatal neurons and circuits. This review describes and summarizes several developmental, cellular, structural, and connectional features of the primate striatum in relation to patterns of neurodegeneration in the striatum of humans and of non-human primate models. We review (1) the types of neurons in the primate striatum, (2) the cyto-, myelo-, and chemoarchitecture of the primate striatum, (3) the developmental origin of the striatum in light of modern patterning studies, (4) the organization of corticostriatal projections in relation to cortical types, and (5) the topography and time-course of neuron loss, glial reaction, and protein aggregation induced by neurodegenerative diseases in humans and in non-human primate models across striatal sectors and their corresponding cortical areas. We summarize current knowledge about key aspects of primate striatal anatomy and human pathology and indicate knowledge gaps that should be addressed in future studies. We aim to identify factors for selective vulnerability to neurodegeneration of striatal neurons and circuits and obtain hints that could help elucidate striatal pathology in humans.
•Degeneration in the human striatum shows typical time-course and spatial patterns.•Striatal degeneration patterns are distinct for each degenerative disease.•Development, connections, and cytology may underlie striatal degeneration patterns.•Corticostriatal connections may underlie selective vulnerability to Huntington's disease.•Corticostriatal connections provide pathways for Tauopathies and Parkinson's disease.
When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is ...considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.
Parkinson's disease: Oh my gut del Rey, Natalia López‐González; Blesa, Javier
Movement disorders,
March 2017, 2017-03-00, 20170301, Letnik:
32, Številka:
3
Journal Article
Background:
The purpose of the study was to determine the role of fecal calprotectin and lactoferrin in the prediction of inflammatory bowel disease relapses, both in patients with ulcerative colitis ...(UC) and Crohn's disease (CD), in a large, long‐term, follow‐up study.
Methods:
The prospective multicenter study included CD and UC patients who had been in clinical remission for 6 months. At baseline, patients provided a single stool sample for calprotectin and lactoferrin determination. Follow‐up was 12 months in patients showing no relapse and until activity flare in relapsing patients.
Results:
In all, 163 patients (89 CD, 74 UC) were included. Twenty‐six patients (16%) relapsed during follow‐up. Calprotectin concentrations in patients who suffered a relapse were higher than in nonrelapsing patients (239 ± 150 versus 136 ± 158 μg/g; P < 0.001). Relapse risk was higher in patients having high (>150 μg/g) calprotectin concentrations (30% versus 7.8%; P < 0.001) or positive lactoferrin (25% versus 10%; P < 0.05). Fecal calprotectin (>150 μg/g) sensitivity and specificity to predict relapse were 69% and 69%, respectively. Corresponding values for lactoferrin were 62% and 65%, respectively. The area under the receiver operating characteristic curve to predict relapse using calprotectin determination was 0.73 (0.69 for UC and 0.77 for CD). Better results were obtained when only colonic CD disease or only relapses during the first 3 months were considered (100% sensitivity). High fecal calprotectin levels or lactoferrin positivity was associated with clinical relapse in Kaplan–Meier survival analysis, and both fecal tests were associated with relapse in the multivariate analysis.
Conclusions:
Fecal calprotectin and lactoferrin determination may be useful in predicting impending clinical relapse—especially during the following 3 months—in both CD and UC patients. (Inflamm Bowel Dis 2009)
Background
The presence of SARS‐CoV‐2 RNA in plasma has been linked to disease severity and mortality. We compared RT‐qPCR to droplet digital PCR (ddPCR) to detect SARS‐CoV‐2 RNA in plasma from ...COVID‐19 patients (mild, moderate, and critical disease).
Methods
The presence/concentration of SARS‐CoV‐2 RNA in plasma was compared in three groups of COVID‐19 patients (30 outpatients, 30 ward patients and 30 ICU patients) using both RT‐qPCR and ddPCR. Plasma was obtained in the first 24h following admission, and RNA was extracted using eMAG. ddPCR was performed using Bio‐Rad SARS‐CoV‐2 detection kit, and RT‐qPCR was performed using GeneFinder™ COVID‐19 Plus RealAmp Kit. Statistical analysis was performed using Statistical Package for the Social Science.
Results
SARS‐CoV‐2 RNA was detected, using ddPCR and RT‐qPCR, in 91% and 87% of ICU patients, 27% and 23% of ward patients and 3% and 3% of outpatients. The concordance of the results obtained by both methods was excellent (Cohen's kappa index = 0.953). RT‐qPCR was able to detect 34/36 (94.4%) patients positive for viral RNA in plasma by ddPCR. Viral RNA load was higher in ICU patients compared with the other groups (P < .001), by both ddPCR and RT‐qPCR. AUC analysis revealed Ct values (RT‐qPCR) and viral RNA load values (ddPCR) can similarly differentiate between patients admitted to wards and to the ICU (AUC of 0.90 and 0.89, respectively).
Conclusion
Both methods yielded similar prevalence of RNAemia between groups, with ICU patients showing the highest (>85%). RT‐qPCR was as useful as ddPCR to detect and quantify SARS‐CoV‐2 RNAemia in plasma.
Cover Image, Volume 48, Issue 5 Rey, Natalia López‐González; Trigo‐Damas, Inés; Obeso, José A. ...
Neuropathology and applied neurobiology,
August 2022, 2022-08-00, 20220801, Letnik:
48, Številka:
5
Journal Article
Recenzirano
The cover image is based on the Original Article Neuron types in the primate striatum: Stereological analysis of projection neurons and interneurons in control and parkinsonian monkeys by Natalia ...López‐González del Rey et al., https://doi.org/10.1111/nan.12812.
Increasing age is associated with severity and higher mortality of COVID‐19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more ...likely to die. We evaluated the association between relative telomere length (RTL) and COVID‐19 mortality. RTL was measured in patients hospitalized because of COVID‐19. We used Kaplan–Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). Six hundred and eight patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID‐19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted hazard ratio HR (aHR) = 3.33; 95% confidence interval CI = 1.05–10.00; p = 0.040) and at 90 days (aHR = 3.57; 95%CI = 1.23–11.11; p = 0.019). Lower RTL was associated with a higher risk of dying of COVID‐19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population.
Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order to reduce the burden placed on health systems, the situation remains critical. Effective diagnosis, treatment, ...and prophylactic measures are urgently required to meet global demand: recombinant antibodies fulfill these requirements and have marked clinical potential. Here, we describe the fast-tracked development of an alpaca Nanobody specific for the receptor-binding-domain (RBD) of the SARS-CoV-2 Spike protein with potential therapeutic applicability. We present a rapid method for nanobody isolation that includes an optimized immunization regimen coupled with VHH library E. coli surface display, which allows single-step selection of Nanobodies using a simple density gradient centrifugation of the bacterial library. The selected single and monomeric Nanobody, W25, binds to the SARS-CoV-2 S RBD with sub-nanomolar affinity and efficiently competes with ACE-2 receptor binding. Furthermore, W25 potently neutralizes SARS-CoV-2 wild type and the D614G variant with IC50 values in the nanomolar range, demonstrating its potential as antiviral agent.
Autoimmune diseases like celiac disease (CeD) and ulcerative colitis (UC) show a common genetic background defined by the existence of shared susceptibility loci. We aimed to go deeper into this ...common genetic background through performing a cross‐disease study based on gene expression. We measured the expression of 21 genes located in 13 CeD‐UC susceptibility regions, and 10 genes in five CeD risk regions. Determinations were carried out in colon/rectum samples from 13 UC patients (inflamed and uninflamed tissue) and four colon samples from controls. Duodenal samples from 19 CeD patients and 12 controls were used for comparisons. Differences were analyzed using the Bayesian method. The shared chromosomal regions containing TNFAIP3, PTPN2, ICOSLG, C1orf106, and IL21 showed similar results in both diseases. FASLG, PLEK, CCR4, and TAGAP, all located in CeD risk loci, were up‐regulated in both CeD and UC patients. Finally, ZFP36L1, ZMIZ1, PUS10, UBE2L3, and BACH2 showed opposite results in CeD and UC. A high complexity underlies autoimmune common susceptibility loci, as the expression pattern of the studied genes does not always correlate with the one expected attending to the apparent genetic background. Differentially expressed genes such as ZFP36L1, ZMIZ1, PUS10, and BACH2 deserve further research in autoimmune diseases.
Aims
The striatum is mainly composed of projection neurons. It also contains interneurons, which modulate and control striatal output. The aim of the present study was to assess the percentages of ...projection neurons and interneuron populations in the striatum of control monkeys and of parkinsonian monkeys.
Methods
Unbiased stereology was used to estimate the volume density of every neuron population in the caudate, putamen and ventral striatum of control monkeys and of monkeys treated with MPTP, which results in striatal dopamine depletion. The various neuron population phenotypes were identified by immunohistochemistry. All analyses were performed within the same subjects using similar processing and analysis parameters, thus allowing for reliable data comparisons.
Results
In control monkeys, the projection neurons, which express the dopamine‐and‐cAMP‐regulated‐phosphoprotein, 32‐KDa (DARPP‐32), were the most abundant: ~86% of the total neurons counted. The interneurons accounted for the remaining 14%. Among the interneurons, those expressing calretinin were the most abundant (Cr+: ~57%; ~8% of the total striatal neurons counted), followed those expressing Parvalbumin (Pv+: ~18%; 2.6%), dinucleotide phosphate‐diaphorase (NADPH+: ~13%; 1.8%), choline acetyltransferase (ChAT+: ~11%; 1.5%) and tyrosine hydroxylase (TH+: ~0.5%; 0.1%). No significant changes in volume densities occurred in any population following dopamine depletion, except for the TH+ interneurons, which increased in parkinsonian non‐symptomatic monkeys and even more in symptomatic monkeys.
Conclusions
These data are relevant for translational studies targeting specific neuron populations of the striatum. The fact that dopaminergic denervation does not cause neuron loss in any population has potential pathophysiological implications.
The primate striatum contains more interneurons (~14%) than the rodent striatum. Among the interneurons, those expressing calretinin are the most abundant and those expressing tyrosine hydroxylase the least (Cr+ > Pv+ > NADPH+ > ChAT+ > TH+). Dopamine depletion results in no significant density changes in any striatal neurons, except for the TH+, which doubled in monkeys with striatal dopaminergic denervation. These data are relevant to understand the functional connectivity of striatal networks in the normal and dopamine‐depleted striatum.
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