Profiling TREM2 expression in amyotrophic lateral sclerosis.

BACKGROUND AND OBJECTIVES: There is growing evidence of the contribution of neuroinflammation, and in particular microglia, in the pathogenesis of amyotrophic lateral sclerosis (ALS). TREM2 gene plays a crucial role in shaping microglia in neurodegenerative conditions. To deepen the understanding of TREM2 in ALS and investigate the performance of TREM2 as a biomarker, we profiled TREM2 expression levels in spinal cord, cerebrospinal fluid and blood of patients with sporadic ALS. We also wanted to investigate whether the combined measurement of sTREM2 in fluids could improve the diagnostic yield of total and phosphorylated TDP-43 levels. METHODS: We performed a case-control study to profile overall and transcript-specific TREM2 mRNA levels by RT-qPCR and protein expression levels by Western-blot in postmortem specimens of spinal cord from ALS patients and controls. In parallel, we measured soluble TREM2 (sTREM2) protein levels and full length and phosphorylated TDP-43 (tTDP-43 and pTDP-43) by ELISA in CSF and serum from ALS patients vs healthy controls. Patients were prospectively recruited from an ALS unit of a tertiary hospital and fulfilled El Escorial revised criteria. After bivariate analysis, a logistic regression model was developed to identify adjusted estimates of the association of sTREM2 levels in CSF and serum with ALS status. RESULTS: Overall and transcript-specific TREM2 mRNA were upregulated in the spinal cord of ALS patients (n = 21) compared to controls (n = 19). Similar changes were observed in TREM2 protein levels (p < 0.01) in spinal cord of ALS patients vs healthy controls. We also detected significantly higher sTREM2 levels in CSF (p-value < 0.01) of ALS patients (n = 46) vs controls (n = 46) and serum (p-value < 0.001) of ALS patients (n = 100) vs controls (n = 100). In a logistic regression model, both CSF and serum sTREM2 remained independently associated with ALS status with OR = 3.41 (CI 95 %=1.34-8.66) (p-value < 0.05) and OR = 3.38 (CI 95 %: 1.86-6.16) (p-value < 0.001), respectively. We also observed that pTDP-43 levels in CSF is an independent predictor of ALS (p-value < 0.05). CONCLUSIONS: Our results support the role of TREM2 in ALS pathophysiology and demonstrates that the three TREM2 transcripts are deregulated in ALS in postmortem human specimens of spinal cord. We hypothesise about the possible influence of systemic-peripheral inflammation in the disease. Finally, we conclude that pTDP-43 levels in CSF could be a biomarker of ALS, and sTREM2 measurement in CSF and blood emerge as potential non-invasive biomarker in ALS.

Is the Phenotype Designation by PSP-MDS Criteria Stable Throughout the Disease Course and Consistent With Tau Distribution?

INTRODUCTION: The MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones. METHODS: Thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx). RESULTS: Applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed. INTERPRETATION: After the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.

Escolar con malaria por plasmodium falciparum de África: riesgo para la salud pública en Honduras / School child with Plasmodium falciparum malaria from Africa: public health risk in Honduras

Antecedentes: Los viajes a zonas endémicas con parásitos resistentes, la respuesta evolutiva de Plasmodium y los sistemas sanitarios debilitados, comprometen el control mundial y local de la malaria. Descripción del Caso clínico: Niño, 6 años, atendido en Hospital Escuela Universitario (HE), Tegucigalpa, referido desde Siguatepeque, Comayagua, por dudas en diagnóstico de laboratorio y antecedente de vivir en África y cuatro episodios de malaria por P. falciparum (2015-2017). Al ingreso presentó cuadro entérico e informe de Plasmodium spp. Se inició tratamiento con cloroquina, omitida y substituida al día siguiente por derivado de artemisinina al confirmar P. falciparum y 0.7% de eritrocitos parasitados. Presentó buena respuesta clínica y parasitológica, egresando al 7mo día intrahospitalario después de 72 horas afebril. La gota gruesa al egreso informó estadios sexuales de P. falciparum, administrándose primaquina al estar disponible 7 días después. En control ambulatorio al 5to día post-egreso, no se observaron parásitos aunque persistían leucocitos con pigmento malárico fagocitado. Cuatro familiares convivientes en África fueron examinados. El padre, que informó cefalea leve y febrícula, fue detectado con estadios asexuales de P. falciparum; presentó buena respuesta al tratamiento con derivado de artemisinina. Conclusiones: La descripción del caso y los diferentes eslabones en su manejo clínico y epidemiológico, reflejan la potencialidad de complicación de la malaria. La introducción de parásitos resistentes a la cloroquina constituye una amenaza de salud pública, principalmente ante fallas evitables en el sistema sanitario. Es necesario fortalecer el diagnóstico temprano y tratamiento oportuno especialmente en el contexto de la eliminación de malaria en Mesoamérica...(AU)

Hippocampal LMNA Gene Expression is Increased in Late-Stage Alzheimer's Disease.

Lamins are fibrillary proteins that are crucial in maintaining nuclear shape and function. Recently, B-type lamin dysfunction has been linked to tauopathies. However, the role of A-type lamin in neurodegeneration is still obscure. Here, we examined A-type and B-type lamin expression levels by RT-qPCR in Alzheimer's disease (AD) patients and controls in the hippocampus, the core of tau pathology in the brain. LMNA, LMNB1, and LMNB2 genes showed moderate mRNA levels in the human hippocampus with highest expression for the LMNA gene. Moreover, LMNA mRNA levels were increased at the late stage of AD (1.8-fold increase; p-value < 0.05). In addition, a moderate positive correlation was found between age and LMNA mRNA levels (Pearson's r = 0.581, p-value = 0.018) within the control hippocampal samples that was not present in the hippocampal samples affected by AD. A-type and B-type lamin genes are expressed in the human hippocampus at the transcript level. LMNA mRNA levels are up-regulated in the hippocampal tissue in late stages of AD. The effect of age on increasing LMNA expression levels in control samples seems to be disrupted by the development of AD pathology.

PLD3 epigenetic changes in the hippocampus of Alzheimer's disease.

BACKGROUND: Whole-exome sequencing has revealed a rare missense variant in PLD3 gene (rs145999145) to be associated with late onset Alzheimer's disease (AD). Nevertheless, the association remains controversial and little is known about the role of PLD3 in AD. Interestingly, PLD3 encodes a phospholipase that may be involved in amyloid precursor protein (APP) processing. Our aim was to gain insight into the epigenetic mechanisms regulating PLD3 gene expression in the human hippocampus affected by AD. RESULTS: We assessed PLD3 mRNA expression by qPCR and protein levels by Western blot in frozen hippocampal samples from a cohort of neuropathologically confirmed pure AD cases and controls. Next, we profiled DNA methylation at cytosine-phosphate-guanine dinucleotide (CpG) site resolution by pyrosequencing and further validated results by bisulfite cloning sequencing in two promoter regions of the PLD3 gene. A 1.67-fold decrease in PLD3 mRNA levels (p value < 0.001) was observed in the hippocampus of AD cases compared to controls, and a slight decrease was also found by Western blot at protein level. Moreover, PLD3 mRNA levels inversely correlated with the average area of ß-amyloid burden (tau-b = - 0,331; p value < 0.01) in the hippocampus. A differentially methylated region was identified within the alternative promoter of PLD3 gene showing higher DNA methylation levels in the AD hippocampus compared to controls (21.7 ± 4.7% vs. 18.3 ± 4.8%; p value < 0.05). CONCLUSIONS: PLD3 gene is downregulated in the human hippocampus in AD cases compared to controls. Altered epigenetic mechanisms, such as differential DNA methylation within an alternative promoter of PLD3 gene, may be involved in the pathological processes of AD. Moreover, PLD3 mRNA expression inversely correlates with hippocampal ß-amyloid burden, which adds evidence to the hypothesis that PLD3 protein may contribute to AD development by modifying APP processing.

Síndrome hemofagocítico secundario a leishmaniasis visceral en un lactante mayor: reporte de caso / Hemophagocytic síndrome secondary to visceral leishmaniasis in a toddler: report of a case

El síndrome hemofagocítico está caracterizado por la activación anómala del sistema inmune. De etiología primaria o secundaria a enfermedades infecciosas, metabólicas, inmunitarias o neoplásicas. Con incidencia de 0,12 a 1 casos por cada 100 000 niños y una sobrevida de dos meses de no recibir tratamiento. Se diagnostica con 5 de 8 criterios propuestos por la Asociación Internacional de Histocitosis, y tratamiento según etiología. . Se presenta el caso de un paciente masculino de 15 meses de edad, procedente una zona endémica de leishmaniasis (Choluteca, Honduras), que ingresó al Hospital Escuela Universitario con cuadro clínico de fiebre prolongada y hepatoesplenomegalia. En los exámenes auxiliares de detectó: pancitopenia, serología positiva para leishmania, hipertrigliceridemia y valor de ferritina aumentada. Se hizo el diagnóstico de leishmaniasis visceral y síndrome hemofagocítico. Se trató con antimoniato de meglumina por 28 días, metilprednisolona y prednisona; con evolución favorable. El síndrome hem ofagocítico podría ocurrir secundario a leishmaniasis visceral por lo que su diagnóstico debería sospecharse tempranamente para un tratamiento oportuno y mejor pronóstico

The hemophagocytic syndrome is characterized by an abnormal activation of the immune system. This condition may be primary or secondary to infectious, metabolic, immunological, or malignant conditions. Its incidence is 0.12 to 1 case per 100,000 children, and the survival time is around two months with no therapy. The condition is diagnosed with the occurrence of 5 of 8 criteria proposed by the International Histiocytosis Association, and its therapy is according the original etiology. We present the case of a 15-month old male patient, who was brought from Choluteca (an endemic area for leishmaniasis), who was admitted to the University Hospital with prolonged fever and hepatosplenomegaly. Laboratory tests showed pancytopenia, positive serology for Leishmania, hypertriglyceridemia, and increased ferritin levels. Visceral leishmaniasis and hemophagocytic syndrome were diagnosed. The patient received meglumine antimoniate for 28 days, and also methylprednisolone and prednisone; and he had a favorable outcome. The hemophagocytic syndrome may be secondary to visceral leishmaniasis, and its diagnosis should be promptly suspected in order to have timely therapy and a better prognosis